Protein degraders and uses thereof

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same for the targeted degradation of proteins, and the treatment of target protein-mediated disorders.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful for themodulation of targeted ubiquitination, especially with respect to avariety of polypeptides and other proteins, which are degraded and/orotherwise inhibited by compounds according to the present invention. Theinvention also provides pharmaceutically acceptable compositionscomprising compounds of the present invention and methods of using saidcompositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulateskey regulator proteins and degrades misfolded or abnormal proteins. UPPis central to multiple cellular processes, and if defective orimbalanced, it leads to pathogenesis of a variety of diseases. Thecovalent attachment of ubiquitin to specific protein substrates isachieved through the action of E3 ubiquitin ligases. These ligasescomprise over 500 different proteins and are categorized into multipleclasses defined by the structural element of their E3 functionalactivity.

Cereblon (CRBN) interacts with damaged DNA binding protein 1 and formsan E3 ubiquitin ligase complex with Cullin 4 where it functions as asubstrate receptor in which the proteins recognized by CRBN might beubiquitinated and degraded by proteasomes.

Proteasome-mediated degradation of unneeded or damaged proteins plays avery important role in maintaining regular function of a cell, such ascell survival, proliferation and growth. A new role for CRBN has beenidentified; i.e., the binding of immunomodulatory drugs (IMiDs), e.g.thalidomide, to CRBN has now been associated with teratogenicity andalso the cytotoxicity of IMiDs, including lenalidomide, which are widelyused to treat multiple myeloma patients. CRBN is likely a key player inthe binding, ubiquitination and degradation of factors involved inmaintaining function of myeloma cells. These new findings regarding therole of CRBN in IMiD action stimulated intense investigation of CRBN'sdownstream factors involved in maintaining regular function of a cell(Chang and Stewart Int J Biochem Mol Biol. 2011; 2(3): 287-294).

UPP plays a key role in the degradation of short-lived and regulatoryproteins important in a variety of basic cellular processes, includingregulation of the cell cycle, modulation of cell surface receptors andion channels, and antigen presentation. The pathway has been implicatedin several forms of malignancy, in the pathogenesis of several geneticdiseases (including cystic fibrosis, Angelman's syndrome, and Liddlesyndrome), in immune surveillance/viral pathogenesis, and in thepathology of muscle wasting. Many diseases are associated with anabnormal UPP and negatively affect cell cycle and division, the cellularresponse to stress and to extracellular modulators, morphogenesis ofneuronal networks, modulation of cell surface receptors, ion channels,the secretory pathway, DNA repair and biogenesis of organelles.

Aberrations in the process have recently been implicated in thepathogenesis of several diseases, both inherited and acquired. Thesediseases fall into two major groups: (a) those that result from loss offunction with the resultant stabilization of certain proteins, and (b)those that result from gain of function, i.e. abnormal or accelerateddegradation of the protein target.

The UPP is used to induce selective protein degradation, including useof fusion proteins to artificially ubiquitinate target proteins andsynthetic small-molecule probes to induce proteasome-dependentdegradation. Bifunctional compounds composed of a target protein-bindingligand and an E3 ubiquitin ligase ligand, induced proteasome-mediateddegradation of selected proteins via their recruitment to E3 ubiquitinligase and subsequent ubiquitination. These drug-like molecules offerthe possibility of temporal control over protein expression. Suchcompounds are capable of inducing the inactivation of a protein ofinterest upon addition to cells or administration to an animal or human,and could be useful as biochemical reagents and lead to a new paradigmfor the treatment of diseases by removing pathogenic or oncogenicproteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; SchnneklothJ S Jr., Chembiochem, 2005, 6(1):40-46).

An ongoing need exists in the art for effective treatments for disease,especially hyperplasias and cancers, such as multiple myeloma. However,non-specific effects, and the inability to target and modulate certainclasses of proteins altogether, such as transcription factors, remain asobstacles to the development of effective anti-cancer agents. As such,small molecule therapeutic agents that leverage or potentiate cereblon'ssubstrate specificity and, at the same time, are “tunable” such that awide range of protein classes can be targeted and modulated withspecificity would be very useful as a therapeutic. Accordingly, thereremains a need to find bifunctional compounds that are protein degradersuseful as therapeutic agents.

SUMMARY OF THE INVENTION

The present application relates novel bifunctional compounds, whichfunction to recruit targeted proteins to E3 Ubiquitin Ligase fordegradation, and methods of preparation and uses thereof. In particular,the present disclosure provides bifunctional compounds, which findutility as modulators of targeted ubiquitination of a variety ofpolypeptides and other proteins, which are then degraded and/orotherwise inhibited by the bifunctional compounds as described herein.An advantage of the compounds provided herein is that a broad range ofpharmacological activities is possible, consistent with thedegradation/inhibition of targeted polypeptides from virtually anyprotein class or family. In addition, the description provides methodsof using an effective amount of the compounds as described herein forthe treatment or amelioration of a disease condition, such as cancer,e.g., multiple myeloma.

The present application further relates to targeted degradation ofproteins through the use of bifunctional molecules, includingbifunctional molecules that link a cereblon-binding moiety to a ligandthat binds the targeted protein.

The present application also relates to a bifunctional compound havingthe following structure:

wherein,TBM is a target binding moiety capable of binding to the targetedprotein(s);L is a bivalent moiety that connects TBM to UBM; andUBM is a ubiquitin binding moiety capable of binding to a ubiquitinligase such as an E3 Ubiquitin Ligase (e.g., cereblon).

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective for themodulation of targeted ubiquitination. Such compounds have the generalformula I:

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions. Such diseases, disorders, or conditions includethose described herein.

Compounds provided by this invention are also useful for the study ofCRBN and targeted proteins in biological and pathological phenomena; thestudy of CRBN and targeted proteins occurring in bodily tissues; and thecomparative evaluation of new CRBN or targeted protein ligands or otherregulators of CRBN or targeted proteins in vitro or in vivo.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

Compounds of the present invention, and compositions thereof, are usefulfor the modulation of targeted ubiquitination.

As defined herein, the terms “binder,” “modulator,” and “ligand” areused interchangeably and describe a compound that binds to, modulates oris a ligand for CRBN or a targeted protein.

In certain embodiments, the present invention provides a compound offormula I-a:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CH₂— or —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring C, and Ring D is independently a fused ring    selected from 6-membered aryl containing 0-3 nitrogens, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms    independently selected from nitrogen, oxygen or sulfur; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methylene    units of L are independently replaced by —C(D)(H)—, —C(D)₂-, -Cy-,    —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—,    —NRS(O)₂—, —Si(R₂)—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—,    —NRC(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   TBM is a target binding moiety.

Where a point of attachment of

is depicted on Ring B, Ring C, or Ring D, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the ring to which Ring B or Ring C is fused toRing D.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, Ring C,and Ring D, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring B or Ring C are fused to Ring D.

Where a point of attachment of

is depicted on Ring D, it is intended, and one of ordinary skill in theart would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring D including thecarbon atom to which Ring B or Ring C are fused to Ring D.

In certain embodiments, the present invention provides a compound offormula I-a′:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring C, and Ring D is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methylene    units of L are independently replaced by —C(D)(H)—, —C(D)₂-, -Cy-,    —O—, —NR—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—, —P(O)(OR)—, —P(O)(R)—,    —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—,    —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   TBM is a target binding moiety.

Where a point of attachment of

is depicted on Ring B, Ring C, or Ring D, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the ring to which Ring B or Ring C is fused toRing D.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, Ring C,and Ring D, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring B or Ring C are fused to Ring D.

Where a point of attachment of

is depicted on Ring B, Ring C, and Ring D, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring A, including thecarbon atom to which Ring B or Ring C are fused to Ring D.

In certain embodiments, the present invention provides a compound offormula I-b:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a bicyclic ring system selected from

wherein

-   Ring B is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   Ring E is a fused ring selected from a 7-9 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring E is optionally further substituted    with 1-2 oxo groups; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methylene    units of L are independently replaced by —C(D)(H)—, —C(D)₂-, -Cy-,    —O—, —NR—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—, —P(O)(OR)—, —P(O)(R)—,    —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—,    —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   TBM is a target binding moiety.

Where a point of attachment of

is depicted on Ring B or Ring E, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring B and Ring E arefused.

Where a point of attachment of —(R²)_(m) is depicted on Ring B and RingE, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring B and Ring E are fused.

Where a point of attachment of

is depicted on Ring B and Ring E, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring B and Ring E arefused.

In certain embodiments, the present invention provides a compound offormula I-c:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring system selected from

wherein

-   each of Ring F and G is independently a fused ring selected from    6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   Ring H is a fused ring selected from a 7-12 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring H is optionally further substituted    with 1-2 oxo groups;-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methylene    units of L are independently replaced by —C(D)(H)—, —C(D)₂-, -Cy-,    —O—, —NR—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—, —P(O)(OR)—, —P(O)(R)—,    —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—,    —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   TBM is a target binding moiety.

Where a point of attachment of

is depicted on Ring F, Ring G, or Ring H, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring F, Ring G, andRing H are fused.

Where a point of attachment of —(R²)_(m) is depicted on Ring F, Ring G,and Ring H, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring F, Ring G, and Ring H are fused.

Where a point of attachment of

is depicted on Ring F, Ring G, and Ring H, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring F, Ring G, andRing H are fused.

In certain embodiments, the present invention provides a compound offormula I-d:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring D, and Ring C is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —CR₂—, —CFR—, —CF₂—, —NR—, —S—, —S(O)₂— or    —CR═CR—;-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methylene    units of L are independently replaced by —C(D)(H)—, —C(D)₂-, -Cy-,    —O—, —NR—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—, —P(O)(OR)—, —P(O)(R)—,    —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—,    —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   TBM is a target binding moiety.

Where a point of attachment of

is depicted on Ring B, Ring D, or Ring C, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring B, Ring D, orRing C, including the ring to which Ring B or Ring C is fused to Ring D.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, Ring D,or Ring C, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be at anyavailable carbon or nitrogen atom on Ring B, Ring D, or Ring C includingthe carbon atom to which Ring B or Ring C are fused to Ring D.

Where a point of attachment of

is depicted on Ring B, Ring D, or Ring C, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring B, Ring D, orRing C, including the carbon atom to which Ring B or Ring C are fused toRing D.

In certain embodiments, the present invention provides a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring C, and Ring D is independently a fused ring    selected from 6-membered aryl containing 0-3 nitrogens, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms    independently selected from nitrogen, oxygen or sulfur; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methylene    units of L are independently replaced by —C(D)(H)—, —C(D)₂-, -Cy-,    —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—,    —NRS(O)₂—, —Si(R₂)—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—,    —NRC(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   TBM is a target binding moiety.

Where a point of attachment of

is depicted on Ring B, Ring C, or Ring D, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring B or Ring C isfused to Ring D.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, Ring C,and Ring D, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring B or Ring C are fused to Ring D.

Where a point of attachment of

is depicted on Ring D, it is intended, and one of ordinary skill in theart would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring D including thecarbon atom to which Ring B or Ring C are fused to Ring D.

In certain embodiments, the present invention provides a compound offormula II′:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring C, and Ring D is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methylene    units of L are independently replaced by —C(D)(H)—, —C(D)₂-, -Cy-,    —O—, —NR—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—, —P(O)(OR)—, —P(O)(R)—,    —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—,    —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   TBM is a target binding moiety.

Where a point of attachment of

is depicted on Ring B, Ring C, or Ring D, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring B or Ring C isfused to Ring D.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, Ring C,and Ring D, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring B or Ring C are fused to Ring D.

Where a point of attachment of

is depicted on Ring B, Ring C, and Ring D, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring A including thecarbon atom to which Ring B or Ring C are fused to Ring D.

In certain embodiments, the present invention provides a compound offormula II-a:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, —R³, halogen, —CN, —NO₂, —OR,    —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,    —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, or    —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B and Ring C is independently a fused ring selected    from 6-membered aryl containing 0-3 nitrogens, 5 to 7-membered    saturated or partially unsaturated carbocyclyl, 5 to 7-membered    saturated or partially unsaturated heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen or    sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently    selected from nitrogen, oxygen or sulfur;-   Ring D is a fused ring selected from aryl containing 0-3 nitrogens,    saturated or partially unsaturated carbocyclyl, saturated or    partially unsaturated heterocyclyl ring with 1-2 heteroatoms    independently selected from nitrogen, oxygen, silicon, or sulfur, or    heteroaryl with 1-3 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   is a single or double bond;-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methylene    units of L are independently replaced by -Cy-, —O—, —NR—, —S—,    —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —NRS(O)₂—, —Si(R₂)—,    —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   TBM is a target binding moiety.

Where a point of attachment of

is depicted on Ring B, Ring C, or Ring D, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring B or Ring C isfused to Ring D.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, Ring C,and Ring D, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring B or Ring C are fused to Ring D.

Where a point of attachment of

is depicted on Ring D, it is intended, and one of ordinary skill in theart would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring D including thecarbon atom to which Ring B or Ring C are fused to Ring D.

In certain embodiments, the present invention provides a compound offormula II-b:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, —R³, halogen, —CN, —NO₂, —OR,    —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,    —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, or    —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B and Ring C is independently a fused ring selected    from 6-membered aryl containing 0-2 nitrogens, 5 to 7-membered    saturated or partially unsaturated carbocyclyl, 5 to 7-membered    saturated or partially unsaturated heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   is a single or double bond;-   m is 0, 1, 2, 3, 4, 5, 6, 7, or 8;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methylene    units of L are independently replaced by -Cy-, —O—, —NR—, —S—,    —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —NRS(O)₂—, —Si(R₂)—,    —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   TBM is a target binding moiety.

Where a point of attachment of

is depicted on Ring B or Ring C, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring B or Ring C isfused.

Where a point of attachment of —(R²)_(m) is depicted on Ring B or RingC, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom ring to which Ring B or Ring C is fused.

In certain embodiments, the present invention provides a compound offormula II-c:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a bicyclic ring system selected from

wherein

-   Ring B is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   Ring E is a ring selected from a 7-9 membered saturated or partially    unsaturated carbocyclyl or heterocyclyl ring with 1-3 heteroatoms    independently selected from boron, nitrogen, oxygen, silicon, or    sulfur, wherein Ring E is optionally further substituted with 1-2    oxo groups; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methylene    units of L are independently replaced by —C(D)(H)—, —C(D)₂-, -Cy-,    —O—, —NR—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—, —P(O)(OR)—, —P(O)(R)—,    —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—,    —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   TBM is a target binding moiety.

Where a point of attachment of

is depicted on Ring B or Ring E, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring B and Ring E arefused.

Where a point of attachment of —(R²)_(m) is depicted on Ring B and RingE, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring B and Ring E are fused.

Where a point of attachment of

is depicted on Ring B and Ring E, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring B and Ring E arefused.

In certain embodiments, the present invention provides a compound offormula II-d:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring system selected from wherein

-   each of Ring F and G is independently a fused ring selected from    6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   Ring H is a fused ring selected from a 7-12 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring H is optionally further substituted    with 1-2 oxo groups;-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methylene    units of L are independently replaced by —C(D)(H)—, —C(D)₂-, -Cy-,    —O—, —NR—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—, —P(O)(OR)—, —P(O)(R)—,    —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—,    —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   TBM is a target binding moiety.

Where a point of attachment of

is depicted on Ring F, Ring G, or Ring H, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring F, Ring G, andRing H are fused.

Where a point of attachment of —(R²)_(m) is depicted on Ring F, Ring G,and Ring H, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring F, Ring G, and Ring H are fused.

Where a point of attachment of

is depicted on Ring F, Ring G, and Ring H, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring F, Ring G, andRing H are fused.

In certain embodiments, the present invention provides a compound offormula III or IV:

or a pharmaceutically acceptable salt thereof, wherein:

-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,    —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)NR₂, —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,    —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,    —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring D, and Ring C is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —CR₂—, —CFR—, —CF₂—, —NR—, —S—, —S(O)₂— or    —CR═CR—;-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methylene    units of L are independently replaced by —C(D)(H)—, —C(D)₂-, -Cy-,    —O—, —NR—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—, —P(O)(OR)—, —P(O)(R)—,    —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—,    —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   TBM is a target binding moiety; and-   R⁴, R¹⁰, R¹¹, R¹⁵, W¹, W², and X is as defined in WO 2019/099868,    the entirety of each of which is herein incorporated by reference.

Where a point of attachment of

is depicted on Ring B, Ring D, or Ring C, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring B, Ring D, orRing C, including the ring to which Ring B or Ring C is fused to Ring D.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, Ring D,or Ring C, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be at anyavailable carbon or nitrogen atom on Ring B, Ring D, or Ring C includingthe carbon atom to which Ring B or Ring C are fused to Ring D.

Where a point of attachment of

is depicted on Ring B, Ring D, or Ring C, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring B, Ring D, orRing C, including the carbon atom to which Ring B or Ring C are fused toRing D.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C3-C6 hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

As used herein, the term “bridged bicyclic” refers to any bicyclic ringsystem, i.e. carbocyclic or heterocyclic, saturated or partiallyunsaturated, having at least one bridge. As defined by IUPAC, a “bridge”is an unbranched chain of atoms or an atom or a valence bond connectingtwo bridgeheads, where a “bridgehead” is any skeletal atom of the ringsystem which is bonded to three or more skeletal atoms (excludinghydrogen). In some embodiments, a bridged bicyclic group has 7-12 ringmembers and 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Such bridged bicyclic groups are well known in theart and include those groups set forth below where each group isattached to the rest of the molecule at any substitutable carbon ornitrogen atom. Unless otherwise specified, a bridged bicyclic group isoptionally substituted with one or more substituents as set forth foraliphatic groups. Additionally or alternatively, any substitutablenitrogen of a bridged bicyclic group is optionally substituted.Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 9-membered monocyclic or 7- to 11-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl,2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms“heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₄Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘))₂;—N(R^(∘))C(S)NR^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘);—N(R^(∘))N(R^(∘))C(O)R^(∘); —N(R^(∘))N(R^(∘))C(O)NR^(∘))₂;—N(R^(∘))N(R^(∘))C(O)OR^(∘); —(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘);—(CH₂)₀₋₄C(O)OR^(∘); —(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃;—(CH₂)₀₋₄OC(O)R^(∘); —OC(O)(CH₂)₀₋₄SR^(∘); —SC(S)SR^(∘);—(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘);—(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂;—N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘);—P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; —SiR^(∘) ₃; —(C₁₋₄straight or branched alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight orbranched alkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substitutedas defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃ O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —N^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. Representative alkalior alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention. In certainembodiments, a provided compound may be substituted with one or moredeuterium atoms.

As used herein, the term “provided compound” refers to any genus,subgenus, and/or species set forth herein.

As used herein, the term “binder” or “inhibitor” is defined as acompound that binds to CRBN and binds to or inhibits a targeted proteinwith measurable affinity. In certain embodiments, an inhibitor has anIC₅₀ and/or binding constant of less than about 50 μM, less than about 1μM, less than about 500 nM, less than about 100 nM, less than about 10nM, or less than about 1 nM.

A compound of the present invention may be tethered to a detectablemoiety. It will be appreciated that such compounds are useful as imagingagents. One of ordinary skill in the art will recognize that adetectable moiety may be attached to a provided compound via a suitablesubstituent. As used herein, the term “suitable substituent” refers to amoiety that is capable of covalent attachment to a detectable moiety.Such moieties are well known to one of ordinary skill in the art andinclude groups containing, e.g., a carboxylate moiety, an amino moiety,a thiol moiety, or a hydroxyl moiety, to name but a few. It will beappreciated that such moieties may be directly attached to a providedcompound or via a tethering group, such as a bivalent saturated orunsaturated hydrocarbon chain. In some embodiments, such moieties may beattached via click chemistry. In some embodiments, such moieties may beattached via a 1,3-cycloaddition of an azide with an alkyne, optionallyin the presence of a copper catalyst. Methods of using click chemistryare known in the art and include those described by Rostovtsev et al.,Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., BioconjugateChem., 2006, 17, 52-57.

As used herein, the term “detectable moiety” is used interchangeablywith the term “label” and relates to any moiety capable of beingdetected, e.g., primary labels and secondary labels. Primary labels,such as radioisotopes (e.g., tritium, ³²P, ³³P, ³⁵S, or ¹⁴C), mass-tags,and fluorescent labels are signal generating reporter groups which canbe detected without further modifications. Detectable moieties alsoinclude luminescent and phosphorescent groups.

The term “secondary label” as used herein refers to moieties such asbiotin and various protein antigens that require the presence of asecond intermediate for production of a detectable signal. For biotin,the secondary intermediate may include streptavidin-enzyme conjugates.For antigen labels, secondary intermediates may include antibody-enzymeconjugates. Some fluorescent groups act as secondary labels because theytransfer energy to another group in the process of nonradiativefluorescent resonance energy transfer (FRET), and the second groupproduces the detected signal.

The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” asused herein refer to moieties that absorb light energy at a definedexcitation wavelength and emit light energy at a different wavelength.Examples of fluorescent labels include, but are not limited to: AlexaFluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, AlexaFluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, AlexaFluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL,BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568,BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue,Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5),Dansyl, Dapoxyl, Dialkylaminocoumarin,4′,5′-Dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin,Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800),JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin,Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, RhodamineGreen, Rhodamine Red, Rhodol Green,2′,4′,5′,7′-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR),Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

The term “mass-tag” as used herein refers to any moiety that is capableof being uniquely detected by virtue of its mass using mass spectrometry(MS) detection techniques. Examples of mass-tags include electrophorerelease tags such asN-[3-[4′-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecoticAcid, 4′-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and their derivatives. The synthesis and utility of thesemass-tags is described in U.S. Pat. Nos. 4,650,750, 4,709,016,5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270.Other examples of mass-tags include, but are not limited to,nucleotides, dideoxynucleotides, oligonucleotides of varying length andbase composition, oligopeptides, oligosaccharides, and other syntheticpolymers of varying length and monomer composition. A large variety oforganic molecules, both neutral and charged (biomolecules or syntheticcompounds) of an appropriate mass range (100-2000 Daltons) may also beused as mass-tags.

The terms “measurable affinity” and “measurably modulate,” as usedherein, means a measurable change in a CRBN activity between a samplecomprising a compound of the present invention, or composition thereof,and CRBN, and an equivalent sample comprising CRBN, in the absence ofsaid compound, or composition thereof.

3. Description of Exemplary Embodiments

As described above, in certain embodiments, the present inventionprovides a compound of formula I-a:

or a pharmaceutically acceptable salt thereof, wherein L and TBM are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CH₂— or —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, —R³, halogen, —CN, —NO₂, —OR,    —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,    —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, or    —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring C, and Ring D is independently a fused ring    selected from 6-membered aryl containing 0-3 nitrogens, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms    independently selected from nitrogen, oxygen or sulfur; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

As described above, in certain embodiments, the present inventionprovides a compound of formula I-a′:

or a pharmaceutically acceptable salt thereof, wherein L and TBM are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring C, and Ring D is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, a compound of formula I-a′ above is provided as acompound of formula I-a″ or formula I-a′″:

or a pharmaceutically acceptable salt thereof, wherein:each of TBM, L, Ring A, X¹, X², X³, R¹, R², and m is as defined above.

As described above, in certain embodiments, the present inventionprovides a compound of formula I-b:

or a pharmaceutically acceptable salt thereof, wherein L and TBM are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a bicyclic ring system selected from

wherein

-   Ring B is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   Ring E is a ring selected from a 7-9 membered saturated or partially    unsaturated carbocyclyl or heterocyclyl ring with 1-3 heteroatoms    independently selected from boron, nitrogen, oxygen, silicon, or    sulfur, wherein Ring E is optionally further substituted with 1-2    oxo groups; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, a compound of formula I-b above is provided as acompound of formula I-b′ or formula I-b″:

or a pharmaceutically acceptable salt thereof, wherein:each of TBM, L, Ring A, X¹, X², X³, R¹, R², and m is as defined above.

As described above, in certain embodiments, the present inventionprovides a compound of formula I-c:

or a pharmaceutically acceptable salt thereof, wherein L and TBM are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring system selected from

wherein

-   each of Ring F and G is independently a fused ring selected from    6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   Ring H is a fused ring selected from a 7-12 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring H is optionally further substituted    with 1-2 oxo groups;-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, a compound of formula I-c above is provided as acompound of formula I-c′ or formula I-c″:

or a pharmaceutically acceptable salt thereof, wherein:each of TBM, L, Ring A, X¹, X², X³, R¹, R², and m is as defined above.

In certain embodiments, the present invention provides a compound offormula I-d:

or a pharmaceutically acceptable salt thereof, wherein L and TBM are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring D, and Ring C is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —CR₂—, —CFR—, —CF₂—, —NR—, —S—, —S(O)₂— or    —CR═CR—; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, a compound of formula I-d above is provided as acompound of formula I-d′ or formula I-d″:

or a pharmaceutically acceptable salt thereof, wherein:each of TAMBM, Ring E, Ring F, Ring G, L, L¹, R¹, R², X¹, X², X³, and mis as defined above.

As described above, in certain embodiments, the present inventionprovides a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein L and TBM are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, —R³, halogen, —CN, —NO₂, —OR,    —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,    —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, or    —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring C, and Ring D is independently a fused ring    selected from 6-membered aryl containing 0-3 nitrogens, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms    independently selected from nitrogen, oxygen or sulfur; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

As described above, in certain embodiments, the present inventionprovides a compound of formula II′:

or a pharmaceutically acceptable salt thereof, wherein L and TBM are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring C, and Ring D is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, a compound of formula II′ above is provided as acompound of formula II″ or formula II′″:

or a pharmaceutically acceptable salt thereof, wherein:each of TBM, L, Ring A, X¹, R¹, R², and m is as defined above.

As described above, in certain embodiments, the present inventionprovides a compound of formula II-a:

or a pharmaceutically acceptable salt thereof, wherein L and TBM are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, —R³, halogen, —CN, —NO₂, —OR,    —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,    —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, or    —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B and Ring C is independently a fused ring selected    from 6-membered aryl containing 0-3 nitrogens, 5 to 7-membered    saturated or partially unsaturated carbocyclyl, 5 to 7-membered    saturated or partially unsaturated heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen or    sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently    selected from nitrogen, oxygen or sulfur;-   Ring D is a fused ring selected from aryl containing 0-3 nitrogens,    saturated or partially unsaturated carbocyclyl, saturated or    partially unsaturated heterocyclyl ring with 1-2 heteroatoms    independently selected from nitrogen, oxygen, silicon, or sulfur, or    heteroaryl with 1-3 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   is a single or double bond;-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

As described above, in certain embodiments, the present inventionprovides a compound of formula II-b:

or a pharmaceutically acceptable salt thereof, wherein L and TBM are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, —R³, halogen, —CN, —NO₂, —OR,    —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,    —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, or    —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B and Ring C is independently a fused ring selected    from 6-membered aryl containing 0-2 nitrogens, 5 to 7-membered    saturated or partially unsaturated carbocyclyl, 5 to 7-membered    saturated or partially unsaturated heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   is a single or double bond;-   m is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

As described above, in certain embodiments, the present inventionprovides a compound of formula II-c:

or a pharmaceutically acceptable salt thereof, wherein L and TBM are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a bicyclic ring system selected from

wherein

-   Ring B is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   Ring E is a ring selected from a 7-9 membered saturated or partially    unsaturated carbocyclyl or heterocyclyl ring with 1-3 heteroatoms    independently selected from boron, nitrogen, oxygen, silicon, or    sulfur, wherein Ring E is optionally further substituted with 1-2    oxo groups; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, a compound of formula II-c above is provided as acompound of formula II-c′ or formula II-c″:

or a pharmaceutically acceptable salt thereof, wherein:each of TBM, L, Ring A, X¹, R¹, R², and m is as defined above.

In some embodiments, a compound of formula II-c above is provided as acompound of formula II-c-1:

or a pharmaceutically acceptable salt thereof, wherein:each of TBM, L, Ring B, X¹, R¹, R², and m is as defined above.

As described above, in certain embodiments, the present inventionprovides a compound of formula II-d:

or a pharmaceutically acceptable salt thereof, wherein L and TBM are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring system selected from

wherein

-   each of Ring F and G is independently a fused ring selected from    6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   Ring H is a fused ring selected from a 7-12 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring H is optionally further substituted    with 1-2 oxo groups;-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, a compound of formula II-d above is provided as acompound of formula II-d′ or formula II-d″:

or a pharmaceutically acceptable salt thereof, wherein:each of TBM, L, Ring A, X¹, R¹, R², and m is as defined above.

In some embodiments, a compound of formula II-d above is provided as acompound of formula II-d-1:

or a pharmaceutically acceptable salt thereof, wherein L and TBM are asdefined above and described in embodiments herein, and wherein:each of TBM, L, Ring F, Ring G, X¹, R¹, R², and m is as defined above.

In certain embodiments, the present invention provides a compound offormula III or IV:

or a pharmaceutically acceptable salt thereof, wherein L and TBM are asdefined above and described in embodiments herein, and wherein:

-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,    —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)NR₂, —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,    —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,    —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring D, and Ring C is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —CR₂—, —CFR—, —CF₂—, —NR—, —S—, —S(O)₂— or    —CR═CR—;-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;    and-   R⁴, R¹⁰, R¹¹, R¹⁵, W¹, W², and X is as defined in WO 2019/099868,    the entirety of each of which is herein incorporated by reference.

As defined above and described herein, X¹ is a bivalent moiety selectedfrom a covalent bond, —CH₂—, —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—,—P(O)NR₂—, —C(O)—, —C(S)—, or

In some embodiments, X¹ is a covalent bond. In some embodiments, X¹ is—CH₂—. In some embodiments, X¹ is —CHCF₃—. In some embodiments, X¹ is—SO₂—. In some embodiments, X¹ is —S(O)—. In some embodiments, X¹ is—P(O)R—. In some embodiments, X¹ is —P(O)OR—. In some embodiments, X¹ is—P(O)NR₂—. In some embodiments, X¹ is —C(O)—. In some embodiments, X¹ is—C(S)—. In some embodiments, X¹ is

In some embodiments, X¹ is selected from those depicted in Table 1,below.

As defined above and described herein, X² is a carbon atom or siliconatom.

In some embodiments, X² is a carbon atom. In some embodiments, X² is asilicon atom.

In some embodiments, X² is selected from those depicted in Table 1,below.

As defined above and described herein, X³ is a bivalent moiety selectedfrom —CH₂—, —NR—, —O—, —S—, or —Si(R₂)—.

In some embodiments, X³ is —CH₂—. In some embodiments, X³ is —NR—. Insome embodiments, X³ is —O—. In some embodiments, X³ is —S—. In someembodiments, X² is —Si(R₂)—.

In some embodiments, X³ is selected from those depicted in Table 1,below.

As defined above and described herein, R¹ is hydrogen, deuterium,halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR,—P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃, or an optionallysubstituted C₁₋₄ aliphatic.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ isdeuterium. In some embodiments, R¹ is halogen. In some embodiments, R¹is —CN. In some embodiments, le is —OR. In some embodiments, R¹ is —SR.In some embodiments, R¹ is —S(O)R. In some embodiments, R¹ is —S(O)₂R.In some embodiments, R¹ is —NR₂. In some embodiments, R¹ is —P(O)(OR)₂.In some embodiments, R¹ is —P(O)(NR₂)OR. In some embodiments, R¹ is—P(O)(NR₂)₂. In some embodiments, R¹ is —Si(OH)₂R. In some embodiments,R¹ is —Si(OH)(R)₂. In some embodiments, R¹ is —Si(R₃). In someembodiments, R¹ is an optionally substituted C₁₋₄ aliphatic.

In some embodiments, R¹ is selected from those depicted in Table 1,below.

As defined above and described herein, each R is independently hydrogen,or an optionally substituted group selected from C₁₋₆ aliphatic, phenyl,a 4-7 membered saturated or partially unsaturated heterocyclic having1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or: two Rgroups on the same nitrogen are taken together with their interveningatoms to form a 4-7 membered saturated, partially unsaturated, orheteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen,independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is optionallysubstituted C₁₋₆ aliphatic. In some embodiments, R is optionallysubstituted phenyl. In some embodiments, R is optionally substituted 4-7membered saturated or partially unsaturated heterocyclic having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R is optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In some embodiments, two R groups on the samenitrogen are taken together with their intervening atoms to form a 4-7membered saturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected fromnitrogen, oxygen, and sulfur.

In some embodiments, R is selected from those depicted in Table 1,below.

As defined above and described herein, each R² is independentlyhydrogen, —R³, halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —P(O)(OR)₂,—P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂, —Si(R₃), —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR,—C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R.

In some embodiments, R² is hydrogen. In some embodiments, R² is —R³. Insome embodiments, R² is halogen. In some embodiments, R² is —CN. In someembodiments, R² is —NO₂. In some embodiments, R² is —OR. In someembodiments, R² is —SR. In some embodiments, R² is —NR₂. In someembodiments, R² is —P(O)(OR)₂. In some embodiments, R² is —P(O)(NR₂)OR.In some embodiments, R² is —P(O)(NR₂)₂. In some embodiments, R² is—Si(OH)₂R. In some embodiments, R² is —Si(OH)(R)₂. In some embodiments,R² is —Si(R₃). In some embodiments, R² is —S(O)₂R. In some embodiments,R² is —S(O)₂NR₂. In some embodiments, R² is —S(O)R. In some embodiments,R² is —C(O)R. In some embodiments, R² is —C(O)OR. In some embodiments,R² is —C(O)NR₂. In some embodiments, R² is —C(O)N(R)OR. In someembodiments, R² is —C(R)₂N(R)C(O)R. In some embodiments, R² is—C(R)₂N(R)C(O)N(R)₂. In some embodiments, R² is —OC(O)R. In someembodiments, R² is —OC(O)NR₂. In some embodiments, R² is —N(R)C(O)OR. Insome embodiments, R² is —N(R)C(O)R. In some embodiments, R² is—N(R)C(O)NR₂. In some embodiments, R² is —N(R)S(O)₂R.

In some embodiments, R² is —OH. In some embodiments, R² is —NH₂. In someembodiments, R² is —CH₂NH₂. In some embodiments, R² is —CH₂NHCOMe. Insome embodiments, R² is —CH₂NHCONHMe. In some embodiments, R² is—NHCOMe. In some embodiments, R² is —NHCONHEt. In some embodiments, R²is —SiMe₃. In some embodiments, R² is —SiMe₂OH. In some embodiments, R²is —SiMe(OH)₂. In some embodiments, R² is

In some embodiments, R² is Br. In some embodiments, R² is Cl. In someembodiments, R² is F. In some embodiments, R² is Me. In someembodiments, R² is —NHMe. In some embodiments, R² is —NMe₂. In someembodiments, R² is —NHCO₂Et. In some embodiments, R² is —CN. In someembodiments, R² is —CH₂Ph. In some embodiments, R² is —NHCO₂tBu. In someembodiments, R² is —CO₂tBu. In some embodiments, R² is —OMe. In someembodiments, R² is —CF₃.

In some embodiments, R² is selected from those depicted in Table 1,below.

As defined above and described herein, each R³ is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R³ is an optionally substituted C₁₋₆ aliphatic. Insome embodiments, R³ is an optionally substituted phenyl. In someembodiments, R³ is an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R³ is an optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

In some embodiments, R³ is selected from those depicted in Table 1,below.

As defined above and described herein, Ring A is a tricyclic ringselected from

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

As defined above and described herein, Ring A is a bicyclic ring systemselected from

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined above and described herein, each of Ring B, Ring C, and RingD is independently a fused ring selected from 6-membered aryl,6-membered heteroaryl containing 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partiallyunsaturated carbocyclyl, 5 to 7-membered saturated or partiallyunsaturated heterocyclyl ring with 1-3 heteroatoms independentlyselected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-memberedheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen or sulfur.

In some embodiments, each Ring B, Ring C, and Ring D is independently a6-membered aryl. In some embodiments, each Ring B, Ring C, and Ring D isindependently a 6-membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, each Ring B, Ring C, and Ring D is independently a 5 to7-membered saturated or partially unsaturated carbocyclyl. In someembodiments, each Ring B, Ring C, and Ring D is independently a 5 to7-membered saturated or partially unsaturated heterocyclyl with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur. In some embodiments, each Ring B, Ring C, and Ring Dis independently a 5-membered heteroaryl with 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur.

In some embodiments, Ring B, Ring C, and Ring D is selected from thosedepicted in Table 1, below.

As defined above and described herein, Ring E is a ring selected from a7-9 membered saturated or partially unsaturated carbocyclyl orheterocyclyl ring with 1-3 heteroatoms independently selected fromboron, nitrogen, oxygen, silicon, or sulfur, wherein Ring E isoptionally further substituted with 1-2 oxo groups.

In some embodiments, Ring E is a ring selected from a 7-9 memberedsaturated or partially unsaturated carbocyclyl or heterocyclyl ring with1-3 heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur, wherein Ring E is optionally further substitutedwith 1-2 oxo groups.

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is selected from those depicted in Table 1,below.

As defined above and described herein, each of Ring F and Ring G isindependently a fused ring selected from 6-membered aryl, 6-memberedheteroaryl containing 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partiallyunsaturated carbocyclyl, 5 to 7-membered saturated or partiallyunsaturated heterocyclyl ring with 1-3 heteroatoms independentlyselected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-memberedheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen or sulfur

In some embodiments, each of Ring F and Ring G is independently a6-membered aryl. In some embodiments, each of Ring F and Ring G isindependently a 6-membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, each of Ring F and Ring G is independently a 5 to7-membered saturated or partially unsaturated carbocyclyl. In someembodiments, each of Ring F and Ring G is independently a 5 to7-membered saturated or partially unsaturated heterocyclyl ring with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur. In some embodiments, each of Ring F and Ring G isindependently a 5-membered heteroaryl with 1-3 heteroatoms independentlyselected from nitrogen, oxygen or sulfur.

In some embodiments, each Ring F and Ring G is independently

In some embodiments, each Ring F and Ring G is independently

In some embodiments, each Ring F and Ring G is independently

In some embodiments, each Ring F and Ring G is independently

In some embodiments, Ring F and Ring G is independently

In some embodiments, Ring F and Ring G is independently is

In some embodiments, Ring F and Ring G is independently

In some embodiments, Ring F and Ring G is independently

In some embodiments, each of Ring F and G is independently selected fromthose depicted in Table 1, below.

As defined above and described herein, Ring H is a fused ring selectedfrom a 7-12 membered saturated or partially unsaturated carbocyclyl orheterocyclyl ring with 1-3 heteroatoms independently selected fromboron, nitrogen, oxygen, silicon, or sulfur, wherein Ring H isoptionally further substituted with 1-2 oxo groups.

In some embodiments, Ring H is a fused ring selected from a 7-12membered saturated or partially unsaturated carbocyclyl. In someembodiments, Ring H is a 7-12 membered saturated or partiallyunsaturated heterocyclyl ring with 1-3 heteroatoms independentlyselected from boron, nitrogen, oxygen, silicon, or sulfur. In someembodiments, Ring H is optionally further substituted with 1-2 oxogroups.

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is selected from those depicted in Table 1,below.

As defined above and described herein, Ring A is a tricyclic ringselected from

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiment, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined above and described herein, Ring D is a fused ring selectedfrom aryl containing 0-3 nitrogens, saturated or partially unsaturatedcarbocyclyl, saturated or partially unsaturated heterocyclyl ring with1-2 heteroatoms independently selected from nitrogen, oxygen, silicon,or sulfur, or heteroaryl with 1-3 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur.

In some embodiments, Ring D is an aryl containing 0-2 nitrogen atoms. Insome embodiments, Ring D is a saturated or partially unsaturatedcarbocyclyl. In some embodiments, each Ring D is a saturated orpartially unsaturated heterocyclyl with 1-2 heteroatoms independentlyselected from nitrogen, oxygen, silicon, or sulfur. In some embodiments,Ring D is a heteroaryl with 1-3 heteroatoms independently selected fromnitrogen, oxygen or sulfur.

In some embodiments. Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is selected from those depicted in Table 1,below.

As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4. In some embodiments, m is 5. In some embodiments, m is 6. In someembodiments, m is 7. In some embodiments, m is 8. In some embodiments, mis 9. In some embodiments, m is 10. In some embodiments, m is 11. Insome embodiments, m is 12. In some embodiments, m is 13. In someembodiments, m is 14. In some embodiments, m is 15. In some embodiments,m is 16.

In some embodiments, m is selected from those depicted in Table 1,below.

As defined above and described herein, Ring A is a tricyclic ringselected from

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiment, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined above and described herein, each Ring B and Ring C isindependently a fused ring selected from 6-membered aryl containing 0-2nitrogen atoms, 5 to 7-membered saturated or partially unsaturatedcarbocyclyl, 5 to 7-membered saturated or partially unsaturatedheterocyclyl with 1-3 heteroatoms independently selected from boron,nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-3heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, each Ring B and Ring C is independently a6-membered aryl containing 0-2 nitrogen atoms. In some embodiments, eachRing B and Ring C is independently a 5 to 7-membered saturated orpartially unsaturated carbocyclyl. In some embodiments, each Ring B andRing C is independently a 5 to 7-membered saturated or partiallyunsaturated heterocyclyl with 1-3 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments,each Ring B and Ring C is independently a 5-membered heteroaryl with 1-3heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, each Ring B and Ring C is independently

In some embodiments, each Ring B and Ring C is independently

In some embodiments, each Ring B and Ring C is independently

In some embodiments, each Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently is

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently In someembodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently selected fromthose depicted in Table 1, below.

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined above and described herein,

is a single or double bond

In some embodiments,

is a single bond. In some embodiments,

is a double bond.

As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, or8.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4. In some embodiments, m is 5. In some embodiments, m is 6. In someembodiments, m is 7. In some embodiments, m is 8.

In some embodiments, m is selected from those depicted in Table 1,below.

As defined above and described herein, L is a covalent bond or abivalent, saturated or unsaturated, straight or branched C₁₋₅₀hydrocarbon chain, wherein 0-6 methylene units of L are independentlyreplaced by —C(D)(H)—, —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—,—Si(OH)(R)—, —Si(OH)₂—, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—,—OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—,—N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, —N(R)C(O)O—,

and wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some embodiments, L is a covalent bond. In some embodiments, L is abivalent, saturated or unsaturated, straight or branched C₁₋₅₀hydrocarbon chain, wherein 0-6 methylene units of L are independentlyreplaced by —C(D)(H)—, —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(OH)(R)—,—Si(OH)₂—, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—,—C(O)—, —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—,—C(O)N(R)—, —OC(O)N(R)—, —N(R)C(O)O—,

and wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

As defined above and described herein, each -Cy- is independently anoptionally substituted bivalent ring selected from phenylenyl, an 8-10membered bicyclic arylenyl, a 4-7 membered saturated or partiallyunsaturated carbocyclylenyl, a 4-7 membered saturated or partiallyunsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturatedor partially unsaturated carbocyclylenyl, a 4-7 membered saturated orpartially unsaturated heterocyclylenyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, a 4-7 memberedsaturated or partially unsaturated spiro heterocyclylenyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, an8-10 membered bicyclic saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur, oran 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, -Cy- is an optionally substituted phenylenyl. Insome embodiments, -Cy- is an optionally substituted 8-10 memberedbicyclic arylenyl. In some embodiments, -Cy- is an optionallysubstituted 4-7 membered saturated or partially unsaturatedcarbocyclylenyl. In some embodiments, -Cy- is an optionally substituted4-7 membered saturated or partially unsaturated spiro carbocyclylenyl.In some embodiments, -Cy- is an optionally substituted 8-10 memberedbicyclic saturated or partially unsaturated carbocyclylenyl. In someembodiments, -Cy- is an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclylenyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, -Cy- is an optionally substituted 4-7 membered saturated orpartially unsaturated spiro heterocyclylenyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, -Cy- is an optionally substituted 8-10 membered bicyclicsaturated or partially unsaturated heterocyclylenyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, -Cy- is an optionally substituted 5-6 memberedheteroarylenyl having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, -Cy- is an optionallysubstituted 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy-is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is selected from those depicted in Table 1,below.

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

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In some embodiments, L is a covalent bond. In some embodiments, L is

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embodiments, L is

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some embodiments, L is a covalent bond. In some embodiments, L is

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In some embodiments, L is selected from those depicted in Table 1,below.

As defined above and described herein, TBM is a target binding moiety.

In some embodiments, TBM is a target binding moiety.

In some embodiments. TBM binds to a protein selected from those listedin paragraph [00236].

In some embodiments, TBM is selected from one of the drugs listed inTable 2, wherein the drug is attached to

at any modifiable carbon, oxygen, sulfur or nitrogen atom.

In some embodiments, TBM is

In some embodiments, TBM is

In some embodiments, TBM is

In some embodiments, TBM is

In some embodiments, TBM is

In some embodiments, TBM is

In some embodiments, TBM is

In some embodiments, TBM is

In some embodiments, TBM is selected from those depicted in Table 1,below.

In preferred aspects of the invention, the TBM group is a group, whichbinds to target proteins. Targets of the TBM group are numerous in kindand are selected from proteins that are expressed in a cell such that atleast a portion of the sequences is found in the cell and may bind to aTBM group. The term “protein” includes oligopeptides and polypeptidesequences of sufficient length that they can bind to a TBM groupaccording to the present invention. Any protein in a eukaryotic system,as described herein, are targets for ubiquitination mediated by thecompounds according to the present invention.

TBM groups according to the present invention include, for example,include any moiety which binds to a protein specifically (binds to atarget protein) and includes the following non-limiting examples ofsmall molecule target protein moieties: Hsp90 inhibitors, kinaseinhibitors, HDM2 & MDM2 inhibitors, compounds targeting Human BETBromodomain-containing proteins, HDAC inhibitors, human lysinemethyltransferase inhibitors, angiogenesis inhibitors, nuclear hormonereceptor compounds, immunosuppressive compounds, and compounds targetingthe aryl hydrocarbon receptor (AHR), among numerous others. Thecompositions described below exemplify some of the members of these ninetypes of small molecule target protein binding moieties. Such smallmolecule target protein binding moieties also include pharmaceuticallyacceptable salts, enantiomers, solvates and polymorphs of thesecompositions, as well as other small molecules that may target a proteinof interest. These binding moieties are linked to the ubiquitin ligasebinding moiety preferably through a linker in order to present a targetprotein (to which the protein target moiety is bound) in proximity tothe ubiquitin ligase for ubiquitination and degradation.

Any protein, which can bind to a target binding moiety or TBM group andacted on or degraded by an ubiquitin ligase is a target proteinaccording to the present invention. In general, target proteins mayinclude, for example, structural proteins, receptors, enzymes, cellsurface proteins, proteins pertinent to the integrated function of acell, including proteins involved in catalytic activity, aromataseactivity, motor activity, helicase activity, metabolic processes(anabolism and catabolism), antioxidant activity, proteolysis,biosynthesis, proteins with kinase activity, oxidoreductase activity,transferase activity, hydrolase activity, lyase activity, isomeraseactivity, ligase activity, enzyme regulator activity, signal transduceractivity, structural molecule activity, binding activity (protein, lipidcarbohydrate), receptor activity, cell motility, membrane fusion, cellcommunication, regulation of biological processes, development, celldifferentiation, response to stimulus, behavioral proteins, celladhesion proteins, proteins involved in cell death, proteins involved intransport (including protein transporter activity, nuclear transport,ion transporter activity, channel transporter activity, carrieractivity, permease activity, secretion activity, electron transporteractivity, pathogenesis, chaperone regulator activity, nucleic acidbinding activity, transcription regulator activity, extracellularorganization and biogenesis activity, translation regulator activity.Proteins of interest can include proteins from eukaryotes andprokaryotes including humans as targets for drug therapy, other animals,including domesticated animals, microbials for the determination oftargets for antibiotics and other antimicrobials and plants, and evenviruses, among numerous others.

TBM (or target binding moiety) is a small molecule which is capable ofbinding to or binds to a target protein of interest.

Some embodiments of the present application relate to TBMs which includebut are not limited to Hsp90 inhibitors, kinase inhibitors, MDM2inhibitors, compounds targeting Human BET Bromodomain-containingproteins, compounds targeting cytosolic signaling protein FKBP12, HDACinhibitors, human lysine methyltransferase inhibitors, angiogenesisinhibitors, immunosuppressive compounds, and compounds targeting thearyl hydrocarbon receptor (AHR).

In some embodiments, TBM is a BRD ligand selected from

wherein R denotes attachment to

In some embodiments, TBM is a CREBBP ligand selected from

wherein R denotes attachment to

X is N or C; and n is 0 to 8.

In some embodiments, TBM is a SMARCA4/PB1/SMARCA2 ligand selected from

wherein R denotes attachment to

X is N or C; and n is 0 to 8.

In some embodiments, TBM is a TRIM24/BRPF1 ligand selected from

wherein R denotes attachment to

and n is 0 to 8.

In some embodiments, TBM is a glucocorticoid receptor ligand selectedfrom

wherein R denotes attachment to

In some embodiments, TBM is an estrogen/androgen receptor ligandselected from

wherein R denotes attachment to

X is N or C; and n is 0 to 8.

In some embodiments, TBM is a DOT1L ligand selected from

wherein R denotes attachment to

In some embodiments, TBM is a BRAF ligand selected from

wherein R denotes attachment to

In some embodiments, TBM is a Ras ligand selected from

wherein R denotes attachment to

In some embodiments, TBM is a RasG12C ligand selected from

wherein R denotes attachment to

In some embodiments, TBM is a Her3 ligand selected from

wherein R denotes attachment to

and R′ is —CH₂CH₃ or —CH═CH₂.

In some embodiments, TBM is a Bcl-2/Bcl-XL ligand selected from

wherein R denotes attachment to

In some embodiments, TBM is an HDAC ligand selected from

wherein R denotes attachment to

In some embodiments, TBM is a PPAR-gamma ligand selected from

wherein R denotes attachment to

In some embodiments, TBM is selected from

wherein R denotes attachment to

In some embodiments, TBM is an Abl, KRAS, SHP2, cRAF, MerTK or PRMT5ligand that are selected from the following non-limiting examples:

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, TBM is a EZH2 ligand selected from

wherein

denotes attachment to

each of variables R_(PTM(1-4)), W_(PTM), X_(PTM), Y_(PTM), and Z_(PTM)is as defined in WO 2018/119357 and US 2018/0177750, the entirety ofeach of which is herein incorporated by reference.

In some embodiments, TBM is a FLT3 ligand selected from

wherein

denotes attachment to

may be N-substituted.

In some embodiments, a TBM moiety is selected from

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, a TBM moiety is a RAF ligand selected from

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, a TBM moiety is selected from

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, a TBM moiety is selected from

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, a TBM moiety is selected from

wherein ---- denotes attachment to

In some embodiments, a TBM moiety is selected from

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom; Ris 5-(4-methyl-1H-imidazol-1-yl) or 4-(N-ethylpiperazin-1-yl)methyl).

In some embodiments, a TBM moiety is a RAF ligand selected from

wherein ---- denotes attachment to

In some embodiments, a TBM moiety is selected from PTM moieties asrecited in WO 2016/197032 the entirety of which is incorporated hereinby reference. In some embodiments, a TBM moiety is selected from suchinhibitors as described in WO 2016/197032 at paragraphs [00116] through[00173] wherein the recitation of a “Linker” moiety in WO 2016/197032corresponds to the -L- group as defined and described herein. In someembodiments, a TBM moiety is selected from such inhibitors as describedin US 2018/0125821 at paragraphs [0106] through [0115], the entirety ofwhich is incorporated herein by reference. In some embodiments, a TBMmoiety is selected from such inhibitors as described in WO 2018/119441at paragraph [00455], and US 2018/0193470, the entirety of each of whichis herein incorporated by reference. In some embodiments, a TBM moietyis selected from such inhibitors as described in US 2018/0147202, theentirety of which is incorporated herein by reference. In someembodiments, a TBM moiety is selected from such inhibitors as describedin WO 2018/098275 at Table A, the entirety of which is incorporatedherein by reference. In some embodiments, a TBM moiety is selected fromsuch inhibitors as described in WO 2016/169989 and US 2018/0118733, theentirety of each of which is herein incorporated by reference. In someembodiments, a TBM moiety is selected from such inhibitors as describedin WO 2015/181747 and US 2017/0121335, the entirety of each of which isherein incorporated by reference. In some embodiments, a TBM moiety isselected from such inhibitors as described in Shimokawa et al., Med.Chem. Lett., 2017, 8 (10), pp 1042-1047, the entirety of which isincorporated herein by reference. In some embodiments, a TBM moiety isselected from such inhibitors as described in WO 2017/079267 and US2018/0186785, the entirety of each of which is herein incorporated byreference. In some embodiments, a TBM moiety is selected from suchinhibitors as described in Powell et al., J. Med. Chem., 2018, 61 (9),pp 4249-4255, the entirety of which is incorporated herein by reference.In some embodiments, a TBM moiety is selected from such inhibitors asdescribed in Zhang et al., Eur. J. Med. Chem., 2018, 151, pp 304-314,the entirety of which is incorporated herein by reference. In someembodiments, a TBM moiety is selected from such inhibitors as describedin Li et al., Eur. J. Med. Chem., 2018, 151, pp 237-247, the entirety ofwhich is incorporated herein by reference. In some embodiments, a TBMmoiety is selected from such inhibitors as described in WO 2016/169989and US 2018/0118733, the entirety of each of which is hereinincorporated by reference. In some embodiments, a TBM moiety is selectedfrom such inhibitors as described in WO 2017/046036, the entirety ofwhich is incorporated herein by reference. In some embodiments, a TBMmoiety is selected from such inhibitors as described in WO 2016/169989and US 2018/0118733, the entirety of each of which is hereinincorporated by reference. In some embodiments, a TBM moiety is selectedfrom such inhibitors as described in WO 2018/053354 and US 2018/0072711,the entirety of each of which is herein incorporated by reference. Insome embodiments, a TBM moiety is selected from such inhibitors asdescribed in Olsen et al., Nat. Chem. Bio., 2018, 14, pp 163-170, theentirety of which is incorporated herein by reference. In someembodiments, a TBM moiety is selected from such inhibitors as describedin WO 2017/185031, the entirety of which is incorporated herein byreference. In some embodiments, a TBM moiety is selected from suchinhibitors as described in Hatcher et al., Med. Chem. Lett., 2018, 9(6),pp 540-545, the entirety of which is incorporated herein by reference.In some embodiments, a TBM moiety is selected from such inhibitors asdescribed in Burslem et al., Cell Chem. Bio., 2018, 25(1), pp 67-77, theentirety of which is incorporated herein by reference. In someembodiments, a TBM moiety is selected from such inhibitors as describedin CN106977584, the entirety of which is incorporated herein byreference. In some embodiments, a TBM moiety is selected from suchinhibitors as described in WO 2017/197056, the entirety of which isincorporated herein by reference. In some embodiments, a TBM moiety isselected from such inhibitors as described in WO 2018/051107, theentirety of which is incorporated herein by reference. In someembodiments, a TBM moiety is selected from such inhibitors as describedin US 2018/0050021, the entirety of which is incorporated herein byreference. In some embodiments, a TBM moiety is selected from suchinhibitors as described in WO 2017/223452, the entirety of which isincorporated herein by reference. In some embodiments, a TBM moiety isselected from such inhibitors as described in WO 2017/117473, WO2017/117474, and US 2019/0016703, the entirety of each of which isherein incorporated by reference. In some embodiments, a TBM moiety isselected from such inhibitors as described in WO 2018/071606 and US2018/0099940, the entirety of each of which is herein incorporated byreference. In some embodiments, a TBM moiety is selected from suchinhibitors as described in US 2018/0099940, the entirety of which isincorporated herein by reference. In some embodiments, a TBM moiety isselected from such inhibitors as described in Gechijian et al., Nat.Chem. Bio., 2018, 14, pp. 405-412, the entirety of which is incorporatedherein by reference. In some embodiments, a TBM moiety is selected fromsuch inhibitors as described in CN 106749513, the entirety of which isincorporated herein by reference. In some embodiments, a TBM moiety isselected from such inhibitors as described in CN107056772, the entiretyof which is incorporated herein by reference. In some embodiments, a TBMmoiety is selected from such inhibitors as described in Pawar et al.,Cell Rep., 2018, 22(9), pp 2236-2245, the entirety of which isincorporated herein by reference. In some embodiments, a TBM moiety isselected from such inhibitors as described in US 2018/009779, theentirety of which is incorporated herein by reference. In someembodiments, a TBM moiety is selected from such inhibitors as describedin WO 2017/180417, the entirety of which is incorporated herein byreference. In some embodiments, a TBM moiety is selected from suchinhibitors as described in WO 2017/223452, the entirety of which isincorporated herein by reference. In some embodiments, a TBM moiety isselected from such inhibitors as described in US 2018/009779, theentirety of which is incorporated herein by reference. In someembodiments, a TBM moiety is selected from such inhibitors as describedin Tomoshige et al., Bioorg. Med. Chem. Lett., 2018, 28(4), pp 707-710,the entirety of which is incorporated herein by reference. In someembodiments, a TBM moiety is selected from such inhibitors as describedin Chessum et al., J. Med. Chem., 2018, 61(3), pp. 918-933, the entiretyof which is incorporated herein by reference. In some embodiments, a TBMmoiety is selected from such inhibitors as described in CN 105085620,the entirety of which is incorporated herein by reference.

Exemplary compounds of the invention are set forth in Table 1, below.

TABLE 1 Exemplary Compounds I-# Structure I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

In some embodiments, the present invention provides a compound set forthin Table 1, above, or a pharmaceutically acceptable salt thereof.

In some embodiments, TBM is one of the compounds in Table 2, below,wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

Lengthy table referenced here US20220348556A1-20221103-T00001 Pleaserefer to the end of the specification for access instructions.

4. General Methods of Providing the Present Compounds

The compounds of this invention may be prepared or isolated in generalby synthetic and/or semi-synthetic methods known to those skilled in theart for analogous compounds and by methods described in detail in theExamples, herein.

In the Schemes below, where a particular protecting group, leavinggroup, or transformation condition is depicted, one of ordinary skill inthe art will appreciate that other protecting groups, leaving groups,and transformation conditions are also suitable and are contemplated.Such groups and transformations are described in detail in March'sAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B.Smith and J. March, 5^(th) Edition, John Wiley & Sons, 2001,Comprehensive Organic Transformations, R. C. Larock, 2^(nd) Edition,John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,the entirety of each of which is hereby incorporated herein byreference.

As used herein, the phrase “oxygen protecting group” includes, forexample, carbonyl protecting groups, hydroxyl protecting groups, etc.Hydroxyl protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of each of which is herein incorporated by reference. Examplesof suitable hydroxyl protecting groups include, but are not limited to,esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkylethers, and alkoxyalkyl ethers. Examples of such esters includeformates, acetates, carbonates, and sulfonates. Specific examplesinclude formate, benzoyl formate, chloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate,pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate,p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl,9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-(phenyl sulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples ofsuch silyl ethers include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and othertrialkylsilyl ethers. Alkyl ethers include methyl, benzyl,p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, andallyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers includeacetals such as methoxymethyl, methylthiomethyl,(2-methoxyethoxy)methyl, benzyloxymethyl,beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM),3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

Amino protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of each of which is herein incorporated by reference. Suitableamino protecting groups include, but are not limited to, aralkylamines,carbamates, cyclic imides, allyl amines, amides, and the like. Examplesof such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl,methyl oxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc),benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn),fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl,dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl,and the like.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 1 set forth below:

As depicted in Scheme 1, above, amine A-1 is coupled to acid A-2 usingthe coupling agent HATU in the presence of the base DIPEA in DMF to forma compound of the invention with a linker comprising an amide bond. Thesquiggly bond,

, represents the portion of the linker between TBM and the terminalamino group of A-1 or the portion of the linker between UBM and theterminal carboxyl group of A-2, respectively. Additionally, an amidebond can be formed using coupling reagents known in the art such as, butnot limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl,DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 2 set forth below:

As depicted in Scheme 2, above, amine A-1 is coupled to acid A-2 usingthe coupling agent PyBOP in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising an amide bond.The squiggly bond,

, represents the portion of the linker between TBM and the terminalamino group of A-1 or the portion of the linker between UBM and theterminal carboxyl group of A-2, respectively. Additionally, an amidebond can be formed using coupling reagents known in the art such as, butnot limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl,DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 3 set forth below:

As depicted in Scheme 3, above, acid A-3 is coupled to amine A-4 usingthe coupling agent HATU in the presence of the base DIPEA in DMF to forma compound of the invention with a linker comprising an amide bond. Thesquiggly bond,

, represents the portion of the linker between TBM and the terminalcarboxyl group of A-3 or the portion of the linker between UBM and theterminal amino group of A-4, respectively. Additionally, an amide bondcan be formed using coupling reagents known in the art such as, but notlimited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT,T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 4 set forth below:

As depicted in Scheme 4, above, acid A-3 is coupled to amine A-4 usingthe coupling agent PyBOP in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising an amide bond.The squiggly bond,

, represents the portion of the linker between TBM and the terminalcarboxyl group of A-3 or the portion of the linker between UBM and theterminal amino group of A-4, respectively. Additionally, an amide bondcan be formed using coupling reagents known in the art such as, but notlimited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT,T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 5 set forth below:

As depicted in Scheme 5, above, an S_(N)Ar displacement of fluoride A-6by amine A-5 is effected in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising a secondaryamine. The squiggly bond,

, represents the portion of the linker between TBM and the terminalamino group of A-5.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 6 set forth below:

As depicted in Scheme 6, above, an S_(N)Ar displacement of fluoride A-7by amine A-8 is effected in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising a secondaryamine. The squiggly bond,

, represents the portion of the linker between UBM and the terminalamino group of A-8.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 7 set forth below:

As depicted in Scheme 7, above, reductive amination of the mixture ofaldehyde A-9 and amine A-10 is effected in the presence of NaHB(OAc)₃and KOAc in DMF/THF to form a compound of the invention with a linkercomprising a secondary amine. A linker comprising a tertiary amine canbe prepared similarly using a secondary amine in place of the primaryamine A-10. The squiggly bond,

, represents the portion of the linker between TBM and the terminalaldehyde of A-9 or the portion of the linker between UBM and theterminal amino group of A-10, respectively.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 8 set forth below:

As depicted in Scheme 8, above, reductive amination of the mixture ofaldehyde A-12 and amine A-11 is effected in the presence of NaHB(OAc)₃and KOAc in DMF/THF to form a compound of the invention with a linkercomprising a secondary amine. A linker comprising a tertiary amine canbe prepared similarly using a secondary amine in place of the primaryamine A-11. The squiggly bond,

, represents the portion of the linker between TBM and the terminalamino group of A-11 or the portion of the linker between UBM and theterminal aldehyde of A-12, respectively.

One of skill in the art will appreciate that various functional groupspresent in compounds of the invention such as aliphatic groups,alcohols, carboxylic acids, esters, amides, aldehydes, halogens andnitriles can be interconverted by techniques well known in the artincluding, but not limited to reduction, oxidation, esterification,hydrolysis, partial oxidation, partial reduction, halogenation,dehydration, partial hydration, and hydration. See for example, “March'sAdvanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March,J., John Wiley & Sons, New York: 2001, the entirety of each of which isherein incorporated by reference. Such interconversions may require oneor more of the aforementioned techniques, and certain methods forsynthesizing compounds of the invention are described below in theExemplification.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably bind CRBN, or a mutant thereof, anda targeted protein, or a mutant thereof, in a biological sample or in apatient. In certain embodiments, a composition of this invention isformulated for administration to a patient in need of such composition.In some embodiments, a composition of this invention is formulated fororal administration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

As used herein, the term “active metabolite or residue thereof” meansthat a metabolite or residue thereof is also a binder of CRBN, or amutant thereof, or a targeted protein, or a mutant thereof.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of thecompound can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Presently described are compositions and methods that relate to thesurprising and unexpected discovery that an E3 Ubiquitin Ligase protein,e.g., cereblon, ubiquitinates a target protein once it and the targetprotein are placed in proximity by a bifunctional or chimeric constructthat binds the E3 Ubiquitin Ligase protein and the target protein.Accordingly the present invention provides such compounds andcompositions comprising an E3 Ubiquintin Ligase binding moiety (“UBM”)coupled to a protein target binding moiety (“TBM”), which result in theubiquitination of a chosen target protein, which leads to degradation ofthe target protein by the proteasome.

Compounds and compositions described herein are generally useful for themodulation of targeted ubiquitination, especially with respect to avariety of polypeptides and other proteins, which are degraded and/orotherwise inhibited. In some embodiments the protein inhibited by thecompounds and methods of the invention comprises those proteins listedin paragraph [00236].

Compounds and compositions described herein exhibit a broad range ofpharmacological activities, consistent with the degradation/inhibitionof targeted polypeptides.

Accordingly, compounds that bind CRBN are beneficial, especially thosewith selectivity over E3 ligases. Such compounds should deliver apharmacological response that favorably treats one or more of theconditions described herein without the side-effects associated with thebinding of E3 ligases.

Even though CRBN binders are known in the art, there is a continuingneed to provide novel binders having more effective or advantageouspharmaceutically relevant properties. For example, compounds withincreased activity, selectivity over other E3 ligases, and ADMET(absorption, distribution, metabolism, excretion, and/or toxicity)properties. Thus, in some embodiments, the present invention providesbinders of CRBN which show selectivity over other E3 ligases.

The activity of a compound utilized in this invention as an binder ofCRBN, or a mutant thereof, may be assayed in vitro, in vivo or in a cellline. In vitro assays include assays that determine the subsequentfunctional consequences, or activity of activated CRBN, or a mutantthereof. Alternate in vitro assays quantitate the ability of thecompound to bind to CRBN. Binding may be measured by radiolabeling thecompound prior to binding, isolating the compound/CRBN complex anddetermining the amount of radiolabel bound. Alternatively, compoundbinding may be determined by running a competition experiment where newcompounds are incubated with CRBN bound to known radioligands.Representative in vitro and in vivo assays useful in assaying a CRBNbinder include those described and disclosed in, Boichenko et al. J.Med. Chem. (2016) 59, 770-774 and Iconomou and Saunders BiochemicalJournal (2016) 473, 4083-4101, each of which is herein incorporated byreference in its entirety. Detailed conditions for assaying a compoundutilized in this invention as an binder of CRBN, or a mutant thereof,are set forth in the Examples below.

The term“Ubiquitin Ligase” refers to a family of proteins thatfacilitate the transfer of ubiquitin to a specific substrate protein,targeting the substrate protein for degradation. For example, cereblonis an E3 Ubiquitin Ligase protein that alone or in combination with anE2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to alysine on a target protein, and subsequently targets the specificprotein substrates for degradation by the proteasome. Thus, E3 ubiquitinligase alone or in complex with an E2 ubiquitin conjugating enzyme isresponsible for the transfer of ubiquitin to targeted proteins. Ingeneral, the ubiquitin ligase is involved in polyubiquitination suchthat a second ubiquitin is attached to the first; a third is attached tothe second, and so forth. Polyubiquitination marks proteins fordegradation by the proteasome. However, there are some ubiquitinationevents that are limited to mono-ubiquitination, in which only a singleubiquitin is added by the ubiquitin ligase to a substrate molecule.Mono-ubiquitinated proteins are not targeted to the proteasome fordegradation, but may instead be altered in their cellular location orfunction, for example, via binding other proteins that have domainscapable of binding ubiquitin. Further complicating matters, differentlysines on ubiquitin can be targeted by an E3 to make chains. The mostcommon lysine is Lys48 on the ubiquitin chain. This is the lysine usedto make polyubiquitin, which is recognized by the proteasome.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

The description provides therapeutic compositions as described hereinfor effectuating the degradation of proteins of interest for thetreatment or amelioration of a disease, e.g., cancer. In certainadditional embodiments, the disease is multiple myeloma. As such, inanother aspect, the description provides a method ofubiquitinating/degrading a target protein in a cell. In certainembodiments, the method comprises administering a bifunctional compoundas described herein comprising, e.g., a UBM and a TBM, linked through alinker moiety, as otherwise described herein, wherein the UBM is coupledto the TBM and wherein the UBM recognizes a ubiquitin pathway protein(e.g., an ubiquitin ligase, preferably an E3 ubiquitin ligase such as,e.g., cereblon) and the TBM recognizes the target protein such thatdegradation of the target protein will occur when the target protein isplaced in proximity to the ubiquitin ligase, thus resulting indegradation/inhibition of the effects of the target protein and thecontrol of protein levels. The control of protein levels afforded by thepresent invention provides treatment of a disease state or condition,which is modulated through the target protein by lowering the level ofthat protein in the cell, e.g., cell of a patient. In certainembodiments, the method comprises administering an effective amount of acompound as described herein, optionally including a pharmaceuticallyacceptable excipient, carrier, adjuvant, another bioactive agent orcombination thereof.

In additional embodiments, the description provides methods for treatingor emeliorating a disease, disorder or symptom thereof in a subject or apatient, comprising administering to a subject in need thereof acomposition comprising an effective amount, e.g., a therapeuticallyeffective amount, of a compound as described herein or salt formthereof, and a pharmaceutically acceptable excipient, carrier, adjuvant,another bioactive agent or combination thereof, wherein the compositionis effective for treating or ameliorating the disease or disorder orsymptom thereof in the subject.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present invention.

In another embodiment, the present invention is directed to a method oftreating a human patient in need for a disease state or conditionmodulated through a protein where the degradation of that protein willproduce a therapeutic effect in that patient, the method comprisingadministering to a patient in need an effective amount of a compoundaccording to the present invention, optionally in combination withanother bioactive agent. The disease state or condition may be a diseasecaused by a microbial agent or other exogenous agent such as a virus,bacteria, fungus, protozoa or other microbe or may be a disease state,which is caused by overexpression of a protein, which leads to a diseasestate and/or condition.

Disease states of conditions which may be treated using compoundsaccording to the present invention include, for example, asthma,autoimmune diseases such as multiple sclerosis, various cancers,ciliopathies, cleft palate, diabetes, heart disease, hypertension,inflammatory bowel disease, mental retardation, mood disorder, obesity,refractive error, infertility, Angelman syndrome, Canavan disease,Coeliac disease, Charcot-Marie-Tooth disease, Cystic fibrosis, Duchennemuscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter'ssyndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease,(PKD1) or 4 (PKD2) Prader-Willi syndrome, Sickle-cell disease, Tay-Sachsdisease, Turner syndrome.

Further disease states or conditions which may be treated by compoundsaccording to the present invention include Alzheimer's disease,Amyotrophic lateral sclerosis (Lou Gehrig's disease), Anorexia nervosa,Anxiety disorder, Atherosclerosis, Attention deficit hyperactivitydisorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronicobstructive pulmonary disease, Crohn's disease, Coronary heart disease,Dementia, Depression, Diabetes mellitus type 1, Diabetes mellitus type2, Epilepsy, Guillain-Barré syndrome, Irritable bowel syndrome, Lupus,Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity,Obsessive-compulsive disorder, Panic disorder, Parkinson's disease,Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Stroke,Thromboangiitis obliterans, Tourette syndrome, Vasculitis.

Still additional disease states or conditions which can be treated bycompounds according to the present invention include aceruloplasminemia,Achondrogenesis type II, achondroplasia, Acrocephaly, Gaucher diseasetype 2, acute intermittent porphyria, Canavan disease, AdenomatousPolyposis Coli, ALA dehydratase deficiency, adenylosuccinate lyasedeficiency, Adrenogenital syndrome, Adrenoleukodystrophy, ALA-Dporphyria, ALA dehydratase deficiency, Alkaptonuria, Alexander disease,Alkaptonuric ochronosis, alpha 1-antitrypsin deficiency, alpha-1proteinase inhibitor, emphysema, amyotrophic lateral sclerosis Alströmsyndrome, Alexander disease, Amelogenesis imperfecta, ALA dehydratasedeficiency, Anderson-Fabry disease, androgen insensitivity syndrome,Anemia Angiokeratoma Corporis Diffusum, Angiomatosis retinae (vonHippel-Lindau disease) Apert syndrome, Arachnodactyly (Marfan syndrome),Stickler syndrome, Arthrochalasis multiplex congenital (Ehlers-Danlossyndrome #arthrochalasia type) ataxia telangiectasia, Rett syndrome,primary pulmonary hypertension, Sandhoff disease, neurofibromatosis typeII, Beare-Stevenson cutis gyrata syndrome, Mediterranean fever,familial, Benjamin syndrome, beta-thalassemia, Bilateral AcousticNeurofibromatosis (neurofibromatosis type II), factor V Leidenthrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloomsyndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome(Turner syndrome), Bourneville disease (tuberous sclerosis), priondisease, Birt-Hogg-Dubé syndrome, Brittle bone disease (osteogenesisimperfecta), Broad Thumb-Hallux syndrome (Rubinstein-Taybi syndrome),Bronze Diabetes/Bronzed Cirrhosis (hemochromatosis), Bulbospinalmuscular atrophy (Kennedy's disease), Burger-Grutz syndrome (lipoproteinlipase deficiency), CGD Chronic granulomatous disorder, Campomelicdysplasia, biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cridu chat, CAVD (congenital absence of the vas deferens), Caylorcardiofacial syndrome (CBAVD), CEP (congenital erythropoieticporphyria), cystic fibrosis, congenital hypothyroidism, Chondrodystrophysyndrome (achondroplasia), otospondylomegaepiphyseal dysplasia,Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome,Thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome,(familial adenomatous polyposis), Congenital erythropoietic porphyria,Congenital heart disease, Methemoglobinemia/Congenitalmethaemoglobinaemia, achondroplasia, X-linked sideroblastic anemia,Connective tissue disease, Conotruncal anomaly face syndrome, Cooley'sAnemia (beta-thalassemia), Copper storage disease (Wilson's disease),Copper transport disease (Menkes disease), hereditary coproporphyria,Cowden syndrome, Craniofacial dysarthrosis (Crouzon syndrome),Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowdensyndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy),Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria,spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophy,Duchenne and Becker types (DBMD), Usher syndrome, Degenerative nervediseases including de Grouchy syndrome and Dejerine-Sottas syndrome,developmental disabilities, distal spinal muscular atrophy, type V,androgen insensitivity syndrome, Diffuse Globoid Body Sclerosis (Krabbedisease), Di George's syndrome, Dihydrotestosterone receptor deficiency,androgen insensitivity syndrome, Down syndrome, Dwarfism, erythropoieticprotoporphyria Erythroid 5-aminolevulinate synthetase deficiency,Erythropoietic porphyria, erythropoietic protoporphyria, erythropoieticuroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis,porphyria cutanea tarda, familial pressure sensitive neuropathy, primarypulmonary hypertension (PPH), Fibrocystic disease of the pancreas,fragile X syndrome, galactosemia, genetic brain disorders, Giant cellhepatitis (Neonatal hemochromatosis), Gronblad-Strandberg syndrome(pseudoxanthoma elasticum), Gunther disease (congenital erythropoieticporphyria), haemochromatosis, Hallgren syndrome, sickle cell anemia,hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease(von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilfordprogeria syndrome (progeria), Hyperandrogenism, Hypochondroplasia,Hypochromic anemia, Immune system disorders, including X-linked severecombined immunodeficiency, Insley-Astley syndrome, Jackson-Weisssyndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weisssyndrome, Kidney diseases, including hyperoxaluria, Klinefelter'ssyndrome, Kniest dysplasia, Lacunar dementia, Langer-Saldinoachondrogenesis, ataxia telangiectasia, Lynch syndrome,Lysyl-hydroxylase deficiency, Machado-Joseph disease, Metabolicdisorders, including Kniest dysplasia, Marfan syndrome, Movementdisorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome,Multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeneychondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffersyndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, Polycystickidney disease, polyostotic fibrous dysplasia (McCune-Albrightsyndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome,hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome),primary pulmonary hypertension, primary senile degenerative dementia,prion disease, progeria (Hutchinson Gilford Progeria Syndrome),progressive chorea, chronic hereditary (Huntington) (Huntington'sdisease), progressive muscular atrophy, spinal muscular atrophy,propionic acidemia, protoporphyria, proximal myotonic dystrophy,pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb(retinoblastoma), Recklinghausen disease (neurofibromatosis type I),Recurrent polyserositis, Retinal disorders, Retinoblastoma, Rettsyndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levysyndrome, severe achondroplasia with developmental delay and acanthosisnigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia, andadrenal gland (SBLA) syndrome, sclerosis tuberose (tuberous sclerosis),SDAT, SED congenital (spondyloepiphyseal dysplasia congenita), SEDStrudwick (spondyloepimetaphyseal dysplasia, Strudwick type), SEDc(spondyloepiphyseal dysplasia congenita) SEMD, Strudwick type(spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzen syndrome,Skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South-Africangenetic porphyria (variegate porphyria), infantile-onset ascendinghereditary spastic paralysis, Speech and communication disorders,sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Sticklersyndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterindeficiency, beta-thalassemia, Thyroid disease, Tomaculous neuropathy(hereditary neuropathy with liability to pressure palsies), TreacherCollins syndrome, Triplo X syndrome (triple X syndrome), Trisomy 21(Down syndrome), Trisomy X, VHL syndrome (von Hippel-Lindau disease),Vision impairment and blindness (Alström syndrome), Vrolik disease,Waardenburg syndrome, Warburg Sjo Fledelius Syndrome,Weissenbacher-Zweymüller syndrome, Wolf-Hirschhorn syndrome, WolffPeriodic disease, Weissenbacher-Zweymüller syndrome and Xerodermapigmentosum, among others.

The term “neoplasia” or“cancer” is used throughout the specification torefer to the pathological process that results in the formation andgrowth of a cancerous or malignant neoplasm, i.e., abnormal tissue thatgrows by cellular proliferation, often more rapidly than normal andcontinues to grow after the stimuli that initiated the new growth cease.Malignant neoplasms show partial or complete lack of structuralorganization and functional coordination with the normal tissue and mostinvade surrounding tissues, metastasize to several sites, and are likelyto recur after attempted removal and to cause the death of the patientunless adequately treated. As used herein, the term neoplasia is used todescribe all cancerous disease states and embraces or encompasses thepathological process associated with malignant hematogenous, ascitic andsolid tumors. Exemplary cancers which may be treated by the presentcompounds either alone or in combination with at least one additionalanti-cancer agent include squamous-cell carcinoma, basal cell carcinoma,adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas,cancer of the bladder, bowel, breast, cervix, colon, esophagus, head,kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach;leukemias; benign and malignant lymphomas, particularly Burkitt'slymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; sarcomas, including Ewing's sarcoma,hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheralneuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using compounds according to the present invention include, forexample, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineagelymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cellLeukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, BurkittsLymphoma, B-cell ALL, Philadelphia chromosome positive ALL andPhiladelphia chromosome positive CML.

In some embodiments, the present invention provides a method fortreating one or more disorders, wherein the disorders are selected fromautoimmune disorders, inflammatory disorders, proliferative disorders,endocrine disorders, neurological disorders, and disorders associatedwith transplantation, said method comprising administering to a patientin need thereof, a pharmaceutical composition comprising an effectiveamount of a compound of the present invention, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, compounds of the present invention induce theubiquitination and degradation of a target protein selected from thegroup consisting of A1BG, A1CF, A2M, A2ML1, A3GALT2, A4GALT, A4GNT,AAAS, AACS, AADAC, AADACL2, AADACL3, AADACL4, AADAT, AAED1, AAGAB, AAK1,AAMDC, AAMP, AANAT, AAR2, AARD, AARS, AARS2, AARSD1, AASDH, AASDHPPT,AASS, AATF, AATK, AATK-AS1, ABAT, ABCA1, ABCA10, ABCA12, ABCA13, ABCA2,ABCA3, ABCA4, ABCA5, ABCA6, ABCA7, ABCA8, ABCA9, ABCB1, ABCB10, ABCB11,ABCB4, ABCB5, ABCB6, ABCB7, ABCB8, ABCB9, ABCC1, ABCC10, ABCC11, ABCC12,ABCC2, ABCC3, ABCC4, ABCC5, ABCC6, ABCC8, ABCC9, ABCD1, ABCD2, ABCD3,ABCD4, ABCE1, ABCF1, ABCF2, ABCF3, ABCG1, ABCG2, ABCG4, ABCG5, ABCG8,ABHD1, ABHD10, ABHD11, ABHD12, ABHD12B, ABHD13, ABHD14A, ABHD14A-ACY1,ABHD14B, ABHD15, ABHD16A, ABHD16B, ABHD17A, ABHD17B, ABHD17C, ABHD18,ABHD2, ABHD3, ABHD4, ABHD5, ABHD6, ABHD8, ABI1, ABI2, ABI3, ABI3BP,ABL1, ABL2, ABLIM1, ABLIM2, ABLIM3, ABO, ABR, ABRA, ABRACL, ABRAXAS1,ABRAXAS2, ABT1, ABTB1, ABTB2, AC001226.2, AC002094.3, AC002115.2,AC002310.4, AC002310.5, AC002429.2, AC002985.1, AC002996.1, AC003002.1,AC003002.2, AC003002.3, AC003002.4, AC003005.1, AC003006.1, AC003688.1,AC004076.1, AC004080.3, AC004223.3, AC004233.2, AC004556.1, AC004691.2,AC004706.4, AC004754.1, AC004805.1, AC004832.3, AC004922.1, AC004997.1,AC005020.2, AC005041.1, AC005154.6, AC005258.1, AC005324.3, AC005324.4,AC005520.1, AC005551.1, AC005670.2, AC005697.1, AC005702.2, AC005726.2,AC005779.2, AC005832.4, AC005833.1, AC005833.3, AC005837.2, AC005841.2,AC005885.1, AC005943.1, AC006030.1, AC006254.1, AC006269.1, AC006449.4,AC006486.1, AC006538.2, AC006978.2, AC007040.2, AC007192.1, AC007240.1,AC007325.1, AC007325.2, AC007325.4, AC007326.4, AC007375.2, AC007383.6,AC007537.5, AC007731.5, AC007906.2, AC007998.2, AC008073.3, AC008162.2,AC008393.2, AC008403.1, AC008481.3, AC008537.1, AC008560.1, AC008575.1,AC008575.2, AC008687.1, AC008687.4, AC008687.8, AC008695.1, AC008735.6,AC008750.8, AC008758.1, AC008758.4, AC008758.5, AC008758.6, AC008763.2,AC008763.3, AC008764.1, AC008764.4, AC008770.2, AC008770.3, AC008878.1,AC008878.2, AC008878.3, AC008982.1, AC008982.3, AC009014.1, AC009086.2,AC009119.2, AC009122.1, AC009133.6, AC009163.2, AC009163.4, AC009286.3,AC009336.2, AC009477.2, AC009690.1, AC009690.3, AC009779.3, AC010132.3,AC010255.3, AC010319.2, AC010323.1, AC010325.1, AC010326.2, AC010327.1,AC010422.3, AC010422.5, AC010422.6, AC010463.1, AC010487.3, AC010522.1,AC010531.1, AC010542.3, AC010547.4, AC010547.5, AC010615.4, AC010616.1,AC010619.1, AC010646.1, AC010724.2, AC011005.1, AC011043.1, AC011043.2,AC011195.2, AC011295.1, AC011346.1, AC011448.1, AC011452.1, AC011455.3,AC011455.4, AC011462.1, AC011473.4, AC011479.1, AC011498.4, AC011499.1,AC011511.1, AC011511.4, AC011530.1, AC011604.2, AC011841.1, AC012184.2,AC012254.2, AC012309.1, AC012314.1, AC012314.10, AC012314.11,AC012314.12, AC012314.4, AC012314.5, AC012314.6, AC012314.8, AC012531.3,AC012651.1, AC013269.1, AC013271.1, AC013394.1, AC013470.2, AC015688.5,AC015802.6, AC015813.2, AC017081.3, AC017081.4, AC017081.5, AC017083.4,AC018512.1, AC018523.2, AC018554.3, AC018630.6, AC018709.1, AC018755.2,AC018793.1, AC018793.2, AC018793.3, AC018793.4, AC018793.5, AC019117.3,AC020636.2, AC020909.1, AC020914.1, AC020915.1, AC020915.2, AC020915.6,AC020922.1, AC020934.3, AC021072.1, AC022016.2, AC022167.5, AC022335.1,AC022384.1, AC022400.6, AC022826.2, AC023055.1, AC023491.2, AC023509.3,AC024592.3, AC024940.1, AC024940.6, AC025165.3, AC025263.2, AC025283.2,AC025287.4, AC025594.2, AC026369.8, AC026398.1, AC026461.4, AC026464.1,AC026464.3, AC026464.4, AC026786.1, AC026954.2, AC027796.3, AC034102.2,AC036214.3, AC037459.1, AC037482.2, AC037482.3, AC040162.1, AC040162.4,AC044810.8, AC046185.1, AC048338.1, AC051649.2, AC053481.5, AC055811.2,AC058822.1, AC064853.2, AC064853.3, AC064853.4, AC064853.5, AC064853.6,AC067968.1, AC068234.1, AC068533.4, AC068547.1, AC068580.4, AC068631.2,AC068775.1, AC068775.2, AC068790.8, AC068896.1, AC068946.1, AC068987.5,AC069257.3, AC069368.1, AC069503.2, AC069544.2, AC072022.1, AC073082.1,AC073111.3, AC073111.5, AC073264.3, AC073508.2, AC073610.2, AC073610.3,AC073612.1, AC073896.1, AC074143.1, AC078927.1, AC079325.2, AC079447.1,AC079594.2, AC083800.1, AC083902.2, AC084337.2, AC087289.3, AC087498.1,AC087632.1, AC090004.1, AC090227.1, AC090360.1, AC090527.2, AC090958.3,AC091167.3, AC091167.7, AC091167.8, AC091304.7, AC091491.1, AC091551.1,AC091959.3, AC091980.2, AC092017.3, AC092042.3, AC092073.1, AC092111.3,AC092143.1, AC092329.3, AC092442.1, AC092587.1, AC092647.5, AC092718.3,AC092718.8, AC092821.1, AC092824.3, AC092835.1, AC093155.3, AC093227.3,AC093423.3, AC093525.1, AC093525.2, AC093668.1, AC093762.1, AC093762.2,AC093762.3, AC093899.2, AC096582.3, AC096887.1, AC097372.1, AC097495.1,AC097637.1, AC097662.2, AC098484.3, AC098650.1, AC098850.4, AC099329.3,AC099489.1, AC099518.3, AC099811.2, AC099850.2, AC100868.1, AC104109.3,AC104151.1, AC104304.1, AC104452.1, AC104532.1, AC104534.3, AC104581.1,AC104581.3, AC104662.2, AC104836.1, AC105001.2, AC105052.1, AC106774.10,AC106774.5, AC106774.6, AC106774.7, AC106774.8, AC106774.9, AC106782.1,AC106886.5, AC107871.1, AC108488.2, AC108750.1, AC108941.2, AC109583.3,AC110275.1, AC112229.3, AC112484.1, AC113189.6, AC113189.9, AC113331.2,AC113554.2, AC114296.1, AC114490.2, AC115220.1, AC116366.3, AC116565.1,AC117457.1, AC118470.1, AC118553.2, AC119396.1, AC119674.2, AC120057.3,AC120114.5, AC124312.1, AC126755.2, AC127537.5, AC127537.6, AC127537.8,AC129492.3, AC131097.2, AC131160.1, AC133551.1, AC133555.3, AC134669.2,AC134772.2, AC135050.2, AC135068.1, AC135068.2, AC135068.3, AC135068.8,AC135178.2, AC135586.2, AC136352.3, AC136352.4, AC136428.1, AC136612.1,AC136616.1, AC136616.2, AC136616.3, AC137834.1, AC138517.2, AC138647.1,AC138696.1, AC138811.2, AC138894.1, AC138969.1, AC139530.2, AC139677.1,AC139677.2, AC140504.1, AC141272.1, AC142391.1, AC142525.4, AC145029.2,AC145212.1, AC145212.2, AC171558.1, AC171558.3, AC171558.5, AC171558.6,AC187653.1, AC207056.1, AC209232.1, AC209539.2, AC210544.1, AC213203.1,AC229888.1, AC229888.10, AC229888.2, AC229888.3, AC229888.4, AC229888.5,AC229888.6, AC229888.7, AC229888.8, AC229888.9, AC233282.1, AC233282.2,AC233723.1, AC233724.12, AC233724.16, AC233724.17, AC233724.18,AC233724.19, AC233724.20, AC233724.21, AC233724.6, AC233755.1,AC233755.2, AC233992.2, AC234301.1, AC234301.3, AC234635.1, AC234635.3,AC234635.4, AC234635.5, AC236040.1, AC239612.1, AC239618.1, AC239618.2,AC239618.3, AC239618.4, AC239618.5, AC239618.6, AC239618.7, AC239618.9,AC239799.1, AC240274.1, AC241401.1, AC241409.2, AC241410.1, AC241556.3,AC241556.4, AC241640.1, AC241640.2, AC241640.4, AC242528.1, AC242528.2,AC243547.3, AC243733.1, AC243734.1, AC243756.1, AC243790.1, AC243967.1,AC244196.1, AC244196.2, AC244196.3, AC244196.4, AC244196.5, AC244197.3,AC244216.4, AC244216.5, AC244226.1, AC244226.2, AC244472.1, AC244472.2,AC244472.3, AC244472.4, AC244472.5, AC244489.1, AC244489.2, AC244517.10,AC244517.6, AC245033.1, AC245034.2, AC245078.1, AC245088.2, AC245088.3,AC245369.1, AC245369.2, AC245369.3, AC245369.4, AC245369.6, AC245427.1,AC245427.3, AC245427.4, AC245427.5, AC245427.6, AC245427.7, AC245427.8,AC245427.9, AC245748.1, AC247036.3, AC247036.4, AC247036.5, AC247036.6,AC254560.1, AC254788.1, AC254788.2, AC254952.1, AC255093.3, AC255093.5,AC256236.1, AC256236.2, AC256236.3, AC256300.2, AC256309.2, AC270107.1,AC270107.10, AC270107.12, AC270107.2, AC270107.3, AC270107.4,AC270107.5, AC270107.7, AC270107.8, AC270107.9, AC270227.1, AC270306.4,AC275455.2, ACAA1, ACAA2, ACACA, ACACB, ACAD10, ACAD11, ACAD8, ACAD9,ACADL, ACADM, ACADS, ACADSB, ACADVL, ACAN, ACAP1, ACAP2, ACAP3, ACAT1,ACAT2, ACBD3, ACBD4, ACBD5, ACBD6, ACBD7, ACCS, ACCSL, ACD, ACE, ACE2,ACER1, ACER2, ACER3, ACHE, ACIN1, ACKR1, ACKR2, ACKR3, ACKR4, ACLY,ACMSD, ACO1, ACO2, ACOD1, ACOT1, ACOT11, ACOT12, ACOT13, ACOT2, ACOT4,ACOT6, ACOT7, ACOT8, ACOT9, ACOX1, ACOX2, ACOX3, ACOXL, ACP1, ACP2,ACP4, ACP5, ACP6, ACP7, ACPP, ACR, ACRBP, ACRV1, ACSBG1, ACSBG2, ACSF2,ACSF3, ACSL1, ACSL3, ACSL4, ACSL5, ACSL6, ACSM1, ACSM2A, ACSM2B, ACSM3,ACSM4, ACSM5, ACSM6, ACSS1, ACSS2, ACSS3, ACTA1, ACTA2, ACTB, ACTBL2,ACTC1, ACTG1, ACTG2, ACTL10, ACTL6A, ACTL6B, ACTL7A, ACTL7B, ACTL8,ACTL9, ACTN1, ACTN2, ACTN3, ACTN4, ACTR10, ACTR1A, ACTR1B, ACTR2, ACTR3,ACTR3B, ACTR3C, ACTR5, ACTR6, ACTR8, ACTRT1, ACTRT2, ACTRT3, ACVR1,ACVR1B, ACVR1C, ACVR2A, ACVR2B, ACVRL1, ACY1, ACY3, ACYP1, ACYP2,AD000671.1, AD000671.2, ADA, ADA2, ADAD1, ADAD2, ADAL, ADAM10, ADAM11,ADAM12, ADAM15, ADAM17, ADAM18, ADAM19, ADAM2, ADAM20, ADAM21, ADAM22,ADAM23, ADAM28, ADAM29, ADAM30, ADAM32, ADAM33, ADAM7, ADAMS, ADAMS,ADAMDEC1, ADAMTS1, ADAMTS10, ADAMTS12, ADAMTS13, ADAMTS14, ADAMTS15,ADAMTS16, ADAMTS17, ADAMTS18, ADAMTS19, ADAMTS2, ADAMTS20, ADAMTS3,ADAMTS4, ADAMTS5, ADAMTS6, ADAMTS7, ADAMTS8, ADAMTS9, ADAMTSL1,ADAMTSL2, ADAMTSL3, ADAMTSL4, ADAMTSL5, ADAP1, ADAP2, ADAR, ADARB1,ADARB2, ADAT1, ADAT2, ADAT3, ADCK1, ADCK2, ADCK5, ADCY1, ADCY10, ADCY2,ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, ADCYAP1, ADCYAP1R1,ADD1, ADD2, ADD3, ADGB, ADGRA1, ADGRA2, ADGRA3, ADGRB1, ADGRB2, ADGRB3,ADGRD1, ADGRD2, ADGRE1, ADGRE2, ADGRE3, ADGRES, ADGRF1, ADGRF2, ADGRF3,ADGRF4, ADGRF5, ADGRG1, ADGRG2, ADGRG3, ADGRG4, ADGRG5, ADGRG6, ADGRG7,ADGRL1, ADGRL2, ADGRL3, ADGRL4, ADGRV1, ADH1A, ADH1B, ADH1C, ADH4, ADH5,ADH6, ADH7, ADHFE1, ADI1, ADIG, ADIPOQ, ADIPOR1, ADIPOR2, ADIRF, ADK,ADM, ADM2, ADMS, ADNP, ADNP2, ADO, ADORA1, ADORA2A, ADORA2B, ADORA3,ADPGK, ADPRH, ADPRHL1, ADPRHL2, ADPRM, ADRA1A, ADRA1B, ADRA1D, ADRA2A,ADRA2B, ADRA2C, ADRB1, ADRB2, ADRB3, ADRM1, ADSL, ADSS, ADSSL1, ADTRP,AEBP1, AEBP2, AEN, AES, AF130351.1, AF241726.2, AFAP1, AFAP1L1, AFAP1L2,AFDN, AFF1, AFF2, AFF3, AFF4, AFG1L, AFG3L2, AFM, AFMID, AFP, AFTPH,AGA, AGAP1, AGAP2, AGAP3, AGAP4, AGAP5, AGAPE, AGAP9, AGBL1, AGBL2,AGBL3, AGBL4, AGBL5, AGER, AGFG1, AGFG2, AGGF1, AGK, AGL, AGMAT, AGMO,AGO1, AGO2, AGO3, AGO4, AGPAT1, AGPAT2, AGPAT3, AGPAT4, AGPAT5, AGPS,AGR2, AGR3, AGRN, AGRP, AGT, AGTPBP1, AGTR1, AGTR2, AGTRAP, AGXT, AGXT2,AHCTF1, AHCY, AHCYL1, AHCYL2, AHDC1, AHI1, AHNAK, AHNAK2, AHR, AHRR,AHSA1, AHSA2, AHSG, AHSP, AICDA, AIDA, AIF1, AIF1L, AIFM1, AIFM2, AIFM3,AIG1, AIM2, AIMP1, AIMP2, AIP, AIPL1, AIRE, AJAP1, AJUBA, AK1, AK2, AK3,AK4, AK5, AK6, AK7, AK8, AK9, AKAIN1, AKAP1, AKAP10, AKAP11, AKAP12,AKAP13, AKAP14, AKAP17A, AKAP2, AKAP3, AKAP4, AKAP5, AKAP6, AKAP7,AKAP8, AKAP8L, AKAP9, AKIP1, AKIRIN1, AKIRIN2, AKNA, AKNAD1, AKR1A1,AKR1B1, AKR1B10, AKR1B15, AKR1C1, AKR1C2, AKR1C3, AKR1C4, AKR1D1,AKR1E2, AKR7A2, AKR7A3, AKR7L, AKT1, AKT1S1, AKT2, AKT3, AKTIP,AL020996.2, AL021154.3, AL021546.1, AL021997.3, AL022238.4, AL022318.4,AL024498.2, AL031708.1, AL032819.3, AL033529.1, AL035425.2, AL035460.1,AL049634.2, AL049650.1, AL049697.1, AL049779.1, AL049839.2, AL049844.1,AL049844.3, AL080251.1, AL096814.1, AL096870.1, AL109810.2, AL109811.4,AL109827.1, AL109936.3, AL109936.4, AL110118.2, AL110118.4, AL117258.1,AL117339.5, AL117348.2, AL121581.1, AL121594.3, AL121722.1, AL121753.1,AL121758.1, AL121845.2, AL121845.3, AL132671.2, AL132780.3, AL133352.1,AL133414.1, AL133414.2, AL136295.1, AL136295.3, AL136295.4, AL136295.5,AL136373.1, AL136531.2, AL138694.1, AL138752.2, AL138826.1, AL139011.2,AL139260.3, AL139300.1, AL139353.1, AL157392.5, AL159163.1, AL160275.1,AL160276.1, AL160396.2, AL161669.4, AL161911.1, AL162231.1, AL162231.3,AL163195.3, AL163636.2, AL353572.3, AL353588.1, AL354761.2, AL354822.1,AL355102.2, AL355315.1, AL355860.1, AL355916.3, AL355987.1, AL355987.3,AL356585.9, AL357673.1, AL358075.4, AL359736.1, AL359736.3, AL359922.1,AL360181.3, AL360181.5, AL365205.1, AL365214.3, AL365232.1, AL365273.2,AL391650.1, AL449266.1, AL451007.3, AL512428.1, AL512506.3, AL512785.2,AL513165.2, AL513523.10, AL513523.9, AL583836.1, AL589666.1, AL590132.1,AL590560.1, AL591806.3, AL592183.1, AL592490.1, AL593848.2, AL603832.3,AL645922.1, AL645941.2, AL662828.1, AL662852.6, AL662899.1, AL662899.2,AL662899.3, AL669918.1, AL672043.1, AL672142.1, AL691442.1, AL713999.1,AL772284.2, AL807752.6, AL807752.7, AL844853.2, AL845331.2, AL845464.1,AL928654.4, AL929554.1, AL929561.7, ALAD, ALAS1, ALAS2, ALB, ALCAM,ALDH16A1, ALDH18A1, ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH1L1,ALDH1L2, ALDH2, ALDH3A1, ALDH3A2, ALDH3B1, ALDH3B2, ALDH4A1, ALDH5A1,ALDH6A1, ALDH7A1, ALDH8A1, ALDH9A1, ALDOA, ALDOB, ALDOC, ALG1, ALG10,ALG10B, ALG11, ALG12, ALG13, ALG14, ALG1L, ALG1L2, ALG2, ALG3, ALG5,ALG6, ALG8, ALG9, ALK, ALKALI, ALKAL2, ALKBH1, ALKBH2, ALKBH3, ALKBH4,ALKBH5, ALKBH6, ALKBH7, ALKBH8, ALLC, ALMS1, ALOX12, ALOX12B, ALOX15,ALOX15B, ALOX5, ALOX5AP, ALOXE3, ALPI, ALPK1, ALPK2, ALPK3, ALPL, ALPP,ALPPL2, ALS2, ALS2CL, ALS2CR12, ALX1, ALX3, ALX4, ALYREF, AMACR, AMBN,AMBP, AMBRA1, AMD1, AMDHD1, AMDHD2, AMELX, AMELY, AMER1, AMER2, AMER3,AMFR, AMH, AMHR2, AMIGO1, AMIGO2, AMIGO3, AMMECR1, AMMECR1L, AMN, AMN1,AMOT, AMOTL1, AMOTL2, AMPD1, AMPD2, AMPD3, AMPH, AMT, AMTN, AMY1A,AMY1B, AMY1C, AMY2A, AMY2B, AMZ1, AMZ2, ANAPC1, ANAPC10, ANAPC11,ANAPC13, ANAPC15, ANAPC16, ANAPC2, ANAPC4, ANAPC5, ANAPC7, ANG, ANGEL 1,ANGEL2, ANGPT1, ANGPT2, ANGPT4, ANGPTL1, ANGPTL2, ANGPTL3, ANGPTL4,ANGPTL5, ANGPTL6, ANGPTL7, ANGPTL8, ANHX, ANK1, ANK2, ANK3, ANKAR,ANKDD1A, ANKDD1B, ANKEF1, ANKFN1, ANKFY1, ANKH, ANKHD1, ANKHD1-EIF4EBP3,ANKIB1, ANKK1, ANKLE1, ANKLE2, ANKMY1, ANKMY2, ANKRA2, ANKRD1, ANKRD10,ANKRD11, ANKRD12, ANKRD13A, ANKRD13B, ANKRD13C, ANKRD13D, ANKRD16,ANKRD17, ANKRD18A, ANKRD18B, ANKRD2, ANKRD20A1, ANKRD20A2, ANKRD20A3,ANKRD20A4, ANKRD20A8P, ANKRD22, ANKRD23, ANKRD24, ANKRD26, ANKRD27,ANKRD28, ANKRD29, ANKRD30A, ANKRD30B, ANKRD30BL, ANKRD31, ANKRD33,ANKRD33B, ANKRD34A, ANKRD34B, ANKRD34C, ANKRD35, ANKRD36, ANKRD36B,ANKRD36C, ANKRD37, ANKRD39, ANKRD40, ANKRD42, ANKRD44, ANKRD45, ANKRD46,ANKRD49, ANKRD50, ANKRD52, ANKRD53, ANKRD54, ANKRD55, ANKRD6, ANKRD60,ANKRD61, ANKRD62, ANKRD63, ANKRD65, ANKRD66, ANKRD7, ANKRD9, ANKS1A,ANKS1B, ANKS3, ANKS4B, ANKS6, ANKUB1, ANKZF1, ANLN, ANO1, ANO10, ANO2,ANO3, ANO4, ANO5, ANO6, ANO7, ANO8, ANO9, ANOS1, ANP32A, ANP32B, ANP32D,ANP32E, ANPEP, ANTXR1, ANTXR2, ANTXRL, ANXA1, ANXA10, ANXA11, ANXA13,ANXA2, ANXA2R, ANXA3, ANXA4, ANXA5, ANXA6, ANXA7, ANXA8, ANXA8L1, ANXA9,AOAH, AOC1, AOC2, AOC3, AOX1, AP000275.2, AP000295.1, AP000311.1,AP000322.1, AP000349.1, AP000350.12, AP000350.4, AP000351.3, AP000351.7,AP000721.1, AP000781.2, AP001160.5, AP001273.2, AP001458.2, AP001781.3,AP001931.1, AP002360.1, AP002373.1, AP002495.1, AP002512.3, AP002512.4,AP002748.4, AP002990.1, AP003071.5, AP003108.2, AP003419.2, AP004243.1,AP006285.3, AP1AR, AP1B1, AP1G1, AP1G2, AP1M1, AP1M2, AP1S1, AP1S2,AP1S3, AP2A1, AP2A2, AP2B1, AP2M1, AP2S1, AP3B1, AP3B2, AP3D1, AP3M1,AP3M2, AP3S1, AP3S2, AP4B1, AP4E1, AP4M1, AP4S1, AP5B1, AP5M1, AP5S1,AP5Z1, APAF1, APBA1, APBA2, APBA3, APBB1, APBB1IP, APBB2, APBB3, APC,APC2, APCDD1, APCDD1L, APCS, APEH, APELA, APEX1, APEX2, APH1A, APH1B,API5, APIP, APLF, APLN, APLNR, APLP1, APLP2, APMAP, APOA1, APOA2, APOA4,APOA5, APOB, APOBEC1, APOBEC2, APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D,APOBEC3F, APOBEC3G, APOBEC3H, APOBEC4, APOBR, APOC1, APOC2, APOC3,APOC4, APOC4-APOC2, APOD, APOE, APOF, APOH, APOL1, APOL2, APOL3, APOL4,APOL5, APOL6, APOLD1, APOM, APOO, APOOL, APOPT1, APP, APPBP2, APPL1,APPL2, APRT, APTX, AQP1, AQP10, AQP11, AQP12A, AQP12B, AQP2, AQP3, AQP4,AQP5, AQP6, AQP7, AQP8, AQP9, AQR, AR, ARAF, ARAP1, ARAP2, ARAP3, ARC,ARCN1, AREG, AREL1, ARF1, ARF3, ARF4, ARF5, ARF6, ARFGAP1, ARFGAP2,ARFGAP3, ARFGEF1, ARFGEF2, ARFGEF3, ARFIP1, ARFIP2, ARFRP1, ARG1, ARG2,ARGFX, ARGLU1, ARHGAP1, ARHGAP10, ARHGAP11A, ARHGAP11B, ARHGAP12,ARHGAP15, ARHGAP17, ARHGAP18, ARHGAP19, ARHGAP19-SLIT1, ARHGAP20,ARHGAP21, ARHGAP22, ARHGAP23, ARHGAP24, ARHGAP25, ARHGAP26, ARHGAP27,ARHGAP28, ARHGAP29, ARHGAP30, ARHGAP31, ARHGAP32, ARHGAP33, ARHGAP35,ARHGAP36, ARHGAP39, ARHGAP4, ARHGAP40, ARHGAP42, ARHGAP44, ARHGAP45,ARHGAP5, ARHGAP6, ARHGAP8, ARHGAP9, ARHGDIA, ARHGDIB, ARHGDIG, ARHGEF1,ARHGEF 10, ARHGEF10L, ARHGEF11, ARHGEF12, ARHGEF 15, ARHGEF16, ARHGEF17,ARHGEF18, ARHGEF19, ARHGEF2, ARHGEF25, ARHGEF26, ARHGEF28, ARHGEF3,ARHGEF33, ARHGEF35, ARHGEF37, ARHGEF38, ARHGEF39, ARHGEF4, ARHGEF40,ARHGEF5, ARHGEF6, ARHGEF7, ARHGEF9, ARID1A, ARID1B, ARID2, ARID3A,ARID3B, ARID3C, ARID4A, ARID4B, ARID5A, ARID5B, ARIH1, ARIH2, ARIH2OS,ARL1, ARL10, ARL11, ARL13A, ARL13B, ARL14, ARL14EP, ARL14EPL, ARL15,ARL16, ARL17A, ARL17B, ARL2, ARL2BP, ARL2-SNX15, ARL3, ARL4A, ARL4C,ARL4D, ARL5A, ARL5B, ARL5C, ARL6, ARL6IP1, ARL6IP4, ARL6IP5, ARL6IP6,ARL8A, ARL8B, ARL9, ARMC1, ARMC10, ARMC12, ARMC2, ARMC3, ARMC4, ARMC5,ARMC6, ARMC7, ARMC8, ARMC9, ARMCX1, ARMCX2, ARMCX3, ARMCX4, ARMCX5,ARMCX6, ARMS2, ARMT1, ARNT, ARNT2, ARNTL, ARNTL2, ARPC1A, ARPC1B, ARPC2,ARPC3, ARPC4, ARPC4-TTLL3, ARPC5, ARPC5L, ARPIN, ARPP19, ARPP21, ARR3,ARRB1, ARRB2, ARRDC1, ARRDC2, ARRDC3, ARRDC4, ARRDC5, ARSA, ARSB, ARSD,ARSE, ARSF, ARSG, ARSH, ARSI, ARSJ, ARSK, ART1, ART3, ART4, ART5, ARTN,ARV1, ARVCF, ARX, AS3MT, ASAH1, ASAH2, ASAH2B, ASAP1, ASAP2, ASAP3,ASB1, ASB10, ASB11, ASB12, ASB13, ASB14, ASB15, ASB16, ASB17, ASB18,ASB2, ASB3, ASB4, ASB5, ASB6, ASB7, ASB8, ASB9, ASCC1, ASCC2, ASCC3,ASCL1, ASCL2, ASCL3, ASCL4, ASCL5, ASF1A, ASF1B, ASGR1, ASGR2, ASH1L,ASH2L, ASIC1, ASIC2, ASIC3, ASIC4, ASIC5, ASIP, ASL, ASMT, ASMTL, ASNA1,ASNS, ASNSD1, ASPA, ASPDH, ASPG, ASPH, ASPHD1, ASPHD2, ASPM, ASPN,ASPRV1, ASPSCR1, ASRGL1, ASS1, ASTE1, ASTL, ASTN1, ASTN2, ASXL1, ASXL2,ASXL3, ASZ1, ATAD1, ATAD2, ATAD2B, ATAD3A, ATAD3B, ATAD3C, ATAD5, ATAT1,ATCAY, ATE1, ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, ATF6B, ATF7, ATF7IP,ATF7IP2, ATG10, ATG101, ATG12, ATG13, ATG14, ATG16L1, ATG16L2, ATG2A,ATG2B, ATG3, ATG4A, ATG4B, ATG4C, ATG4D, ATG5, ATG7, ATG9A, ATG9B, ATIC,ATL1, ATL2, ATL3, ATM, ATMIN, ATN1, ATOH1, ATOH7, ATOH8, ATOX1, ATP10A,ATP10B, ATP10D, ATP11A, ATP11B, ATP11C, ATP12A, ATP13A1, ATP13A2,ATP13A3, ATP13A4, ATP13A5, ATP1A1, ATP1A2, ATP1A3, ATP1A4, ATP1B1,ATP1B2, ATP1B3, ATP1B4, ATP23, ATP2A1, ATP2A2, ATP2A3, ATP2B1, ATP2B2,ATP2B3, ATP2B4, ATP2C1, ATP2C2, ATP4A, ATP4B, ATP5A1, ATP5B, ATP5C1,ATP5D, ATP5E, ATP5EP2, ATP5F1, ATP5G1, ATP5G2, ATP5G3, ATP5H, ATP5I,ATP5J, ATP5J2, ATP5J2-PTCD1, ATP5L, ATP5L2, ATP5O, ATP5S, ATP6AP1,ATP6AP1L, ATP6AP2, ATP6V0A1, ATP6V0A2, ATP6V0A4, ATP6V0B, ATP6V0C,ATP6V0D1, ATP6V0D2, ATP6V0E1, ATP6V0E2, ATP6V1A, ATP6V1B1, ATP6V1B2,ATP6V1C1, ATP6V1C2, ATP6V1D, ATP6V1E1, ATP6V1E2, ATP6V1F, ATP6V1G1,ATP6V1G2, ATP6V1G2-DDX39B, ATP6V1G3, ATP6V1H, ATP7A, ATP7B, ATP8A1,ATP8A2, ATP8B1, ATP8B2, ATP8B3, ATP8B4, ATP9A, ATP9B, ATPAF1, ATPAF2,ATPIF1, ATR, ATRAID, ATRIP, ATRN, ATRNL1, ATRX, ATXN1, ATXN10, ATXN1L,ATXN2, ATXN2L, ATXN3, ATXN3L, ATXN7, ATXN7L1, ATXN7L2, ATXN7L3,ATXN7L3B, AUH, AUNIP, AUP1, AURKA, AURKAIP1, AURKB, AURKC, AUTS2, AVEN,AVIL, AVL9, AVP, AVPI1, AVPR1A, AVPR1B, AVPR2, AWAT1, AWAT2, AXDND1,AXIN1, AXIN2, AXL, AZGP1, AZI2, AZIN1, AZIN2, AZU1, B2M, B3GALNT1,B3GALNT2, B3GALT1, B3GALT2, B3GALT4, B3GALT5, B3GALT6, B3GAT1, B3GAT2,B3GAT3, B3GLCT, B3GNT2, B3GNT3, B3GNT4, B3GNT5, B3GNT6, B3GNT7, B3GNT8,B3GNT9, B3GNTL1, B4GALNT1, B4GALNT2, B4GALNT3, B4GALNT4, B4GALT1,B4GALT2, B4GALT3, B4GALT4, B4GALT5, B4GALT6, B4GALT7, B4GAT1, B9D1,B9D2, BAALC, BAAT, BABAM1, BABAM2, BACE1, BACE2, BACH1, BACH2, BAD,BAG1, BAG2, BAG3, BAG4, BAG5, BAG6, BAGE3, BAHCC1, BAHD1, BAIAP2,BAIAP2L1, BAIAP2L2, BAIAP3, BAK1, BAMBI, BANF1, BANF2, BANK1, BANP,BAP1, BARD1, BARHL1, BARHL2, BARX1, BARX2, BASP1, BATF, BATF2, BATF3,BAX, BAZ1A, BAZ1B, BAZ2A, BAZ2B, BBC3, BBIP1, BBOF1, BBOX1, BBS1, BBS10,BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, BBX, BCAM, BCAN, BCAP29, BCAP31,BCAR1, BCAR3, BCAS1, BCAS2, BCAS3, BCAS4, BCAT1, BCAT2, BCCIP, BCDIN3D,BCHE, BCKDHA, BCKDHB, BCKDK, BCL10, BCL11A, BCL11B, BCL2, BCL2A1,BCL2L1, BCL2L10, BCL2L11, BCL2L12, BCL2L13, BCL2L14, BCL2L15, BCL2L2,BCL2L2-PABPN1, BCL3, BCL6, BCL6B, BCL7A, BCL7B, BCL7C, BCL9, BCL9L,BCLAF1, BCLAF3, BCO1, BCO2, BCOR, BCORL1, BCR, BCS1L, BDH1, BDH2,BDKRB1, BDKRB2, BDNF, BDP1, BEAN1, BECN1, BECN2, BEGAIN, BEND2, BEND3,BEND4, BEND5, BEND6, BEND7, BEST1, BEST2, BEST3, BEST4, BET1, BET1L,BEX1, BEX2, BEX3, BEX4, BEX5, BFAR, BFSP1, BFSP2, BGLAP, BGN, BHLHA15,BHLHA9, BHLHB9, BHLHE22, BHLHE23, BHLHE40, BHLHE41, BHMG1, BHMT, BHMT2,BICC1, BICD1, BICD2, BICDL1, BICDL2, BICRA, BICRAL, BID, BIK, BIN1,BIN2, BIN3, BIRC2, BIRC3, BIRC5, BIRC6, BIRC7, BIRC8, BIVM, BIVM-ERCC5,BLACE, BLCAP, BLID, BLK, BLM, BLMH, BLNK, BLOC1S1, BLOC1S2, BLOC1S3,BLOC1S4, BLOC1S5, BLOC1S5-TXNDC5, BLOC1S6, BLVRA, BLVRB, BLZFL BMF,BMI1, BMP1, BMP10, BMP15, BMP2, BMP2K, BMP3, BMP4, BMP5, BMP6, BMP7,BMP8A, BMP8B, BMPER, BMPR1A, BMPR1B, BMPR2, BMS1, BMT2, BMX, BNC1, BNC2,BNIP1, BNIP2, BNIP3, BNIP3L, BNIPL, BOC, BOD1, BOD1L1, BOD1L2, BOK,BOLA1, BOLA2, BOLA2B, BOLA2-SMG1P6, BOLA3, BOLL, BOP1, BORA, BORCS5,BORCS6, BORCS7, BORCS7-ASMT, BORCS8, BORCS8-MEF2B, BPGM, BPHL, BPI,BPIFA1, BPIFA2, BPIFA3, BPIFB1, BPIFB2, BPIFB3, BPIFB4, BPIFB6, BPIFC,BPNT1, BPTF, BPY2, BPY2B, BPY2C, BRAF, BRAP, BRAT1, BRCA1, BRCA2, BRCC3,BRD1, BRD2, BRD3, BRD4, BRD7, BRD8, BRD9, BRDT, BRF1, BRF2, BRI3,BRI3BP, BRICD5, BRINP1, BRINP2, BRINP3, BRIP1, BRIX1, BRK1, BRMS1,BRMS1L, BROX, BRPF1, BRPF3, BRS3, BRSK1, BRSK2, BRWD1, BRWD3, BSCL2,BSDC1, BSG, BSN, BSND, BSPH1, BSPRY, BST1, BST2, BSX, BTAF1, BTBD1,BTBD10, BTBD11, BTBD16, BTBD17, BTBD18, BTBD19, BTBD2, BTBD3, BTBD6,BTBD7, BTBD8, BTBD9, BTC, BTD, BTF3, BTF3L4, BTG1, BTG2, BTG3, BTG4,BTK, BTLA, BTN1A1, BTN2A1, BTN2A2, BTN3A1, BTN3A2, BTN3A3, BTNL2, BTNL3,BTNL8, BTNL9, BTRC, BUB1, BUB1B, BUB1B-PAK6, BUB3, BUD13, BUD23, BUD31,BVES, BX004987.1, BX072566.1, BX088645.1, BX248244.1, BX248413.4,BX248415.1, BX248516.1, BX276092.9, BYSL, BZW1, BZW2, C10orf10,C10orf105, C10orf107, C10orf113, C10orf120, C10orf126, C10orf128,C10orf142, C10orf35, C10orf53, C10orf55, C10orf62, C10orf67, C10orf71,C10orf76, C10orf82, C10orf88, C10orf90, C10orf95, C10orf99, C11orf1,C11orf16, C11orf21, C11orf24, C11orf40, C11orf42, C11orf45, C11orf49,C11orf52, C11orf53, C11orf54, C11orf57, C11orf58, C11orf63, C11orf65,C11orf68, C11orf70, C11orf71, C11orf74, C11orf80, C11orf84, C11orf86,C11orf87, C11orf88, C11orf91, C11orf94, C11orf95, C11orf96, C11orf97,C11orf98, C12orf10, C12orf29, C12orf4, C12orf40, C12orf42, C12orf43,C12orf45, C12orf49, C12orf50, C12orf54, C12orf56, C12orf57, C12orf60,C12orf65, C12orf66, C12orf71, C12orf73, C12orf74, C12orf75, C12orf76,C13orf42, C14orf105, C14orf119, C14orf132, C14orf159, C14orf166,C14orf177, C14orf178, C14orf180, C14orf2, C14orf28, C14orf37, C14orf39,C14orf79, C14orf80, C14orf93, C15orf38-AP3S2, C15orf39, C15orf40,C15orf41, C15orf48, C15orf52, C15orf53, C15orf59, C15orf61, C15orf62,C15orf65, C16orf45, C16orf46, C16orf52, C16orf54, C16orf58, C16orf59,C16orf62, C16orf70, C16orf71, C16orf72, C16orf74, C16orf78, C16orf82,C16orf86, C16orf87, C16orf89, C16orf90, C16orf91, C16orf92, C16orf95,C16orf96, C17orf100, C17orf105, C17orf107, C17orf113, C17orf47,C17orf49, C17orf50, C17orf51, C17orf53, C17orf58, C17orf62, C17orf64,C17orf67, C17orf74, C17orf75, C17orf78, C17orf80, C17orf97, C17orf98,C17orf99, C18orf21, C18orf25, C18orf32, C18orf54, C18orf63, C18orf8,C19orf12, C19orf18, C19orf24, C19orf25, C19orf33, C19orf35, C19orf38,C19orf44, C19orf47, C19orf48, C19orf53, C19orf54, C19orf57, C19orf60,C19orf66, C19orf67, C19orf68, C19orf70, C19orf71, C19orf73, C19orf81,C19orf4, C1D, C1GALT1, C1GALT1C1, C1GALT1C1L, C1orf100, C1orf105,C1orf109, C1orf112, C1orf115, C1orf116, C1orf122, C1orf123, C1orf127,C1orf131, C1orf141, C1orf146, C1orf158, C1orf159, C1orf162, C1orf167,C1orf174, C1orf185, C1orf186, C1orf189, C1orf194, C1orf198, C1orf21,C1orf210, C1orf216, C1orf226, C1orf228, C1orf232, C1orf27, C1orf35,C1orf43, C1orf50, C1orf52, C1orf53, C1orf54, C1orf56, C1orf61, C1orf64,C1orf68, C1orf74, C1orf87, C1orf94, C1QA, C1QB, C1QBP, C1QC, C1QL1,C1QL2, C1QL3, C1QL4, C1QTNF1, C1QTNF12, C1QTNF2, C1QTNF3, C1QTNF3-AMACR,C1QTNF4, C1QTNF5, C1QTNF6, C1QTNF7, C1QTNF8, C1QTNF9, C1QTNF9B, C1R,C1RL, C1S, C2, C20orf141, C20orf144, C20orf173, C20orf194, C20orf196,C20orf202, C20orf204, C20orf24, C20orf27, C20orf5, C20orf96, C21orf140,C21orf2, C21orf33, C21orf58, C21orf59, C21orf62, C21orf91, C22orf15,C22orf23, C22orf31, C22orf39, C22orf42, C22orf46, C2CD2, C2CD2L, C2CD3,C2CD4A, C2CD4B, C2CD4C, C2CD4D, C2CD5, C2CD6, C2orf15, C2orf16, C2orf40,C2orf42, C2orf49, C2orf50, C2orf54, C2orf66, C2orf68, C2orf69, C2orf70,C2orf71, C2orf72, C2orf73, C2orf74, C2orf76, C2orf78, C2orf80, C2orf81,C2orf82, C2orf83, C2orf88, C2orf91, C3, C3AR1, C3orf14, C3orf18,C3orf20, C3orf22, C3orf30, C3orf33, C3orf35, C3orf36, C3orf38, C3orf49,C3orf52, C3orf56, C3orf58, C3orf62, C3orf67, C3orf70, C3orf80, C3orf34,C3orf85, C4A, C4B, C4B_2, C4BPA, C4BPB, C4orf17, C4orf19, C4orf22,C4orf26, C4orf3, C4orf32, C4orf33, C4orf36, C4orf45, C4orf46, C4orf47,C4orf48, C4orf50, C4orf51, C5, C5AR1, C5AR2, C5orf15, C5orf22, C5orf24,C5orf30, C5orf34, C5orf38, C5orf42, C5orf46, C5orf47, C5orf49, C5orf51,C5orf52, C5orf56, C5orf58, C5orf60, C5orf63, C5orf67, C6, C6orf10,C6orf106, C6orf118, C6orf120, C6orf132, C6orf136, C6orf141, C6orf15,C6orf163, C6orf201, C6orf203, C6orf222, C6orf223, C6orf226, C6orf229,C6orf47, C6orf48, C6orf52, C6orf58, C6orf62, C6orf89, C7, C7orf25,C7orf26, C7orf31, C7orf33, C7orf34, C7orf43, C7orf49, C7orf50,C7orf55-LUC7L2, C7orf57, C7orf61, C7orf72, C7orf73, C7orf77, C8A, C8B,C8G, C8orf22, C8orf33, C8orf34, C8orf37, C8orf4, C8orf44, C8orf44-SGK3,C8orf46, C8orf48, C8orf58, C8orf59, C8orf74, C8orf76, C8orf82, C8orf86,C8orf88, C8orf89, C9, C9orf116, C9orf129, C9orf131, C9orf135, C9orf152,C9orf153, C9orf16, C9orf172, C9orf24, C9orf3, C9orf40, C9orf43, C9orf47,C9orf50, C9orf57, C9orf64, C9orf66, C9orf72, C9orf78, C9orf84, C9orf85,C9orf92, CA1, CA10, CA11, CA12, CA13, CA14, CA2, CA3, CA4, CA5A, CA5B,CA6, CA7, CA8, CA9, CAAP1, CAB39, CAB39L, CABIN1, CABLES1, CABLES2,CABP1, CABP2, CABP4, CABP5, CABP7, CABS1, CABYR, CACFD1, CACHD1,CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H,CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CACNA2D4, CACNB1,CACNB2, CACNB3, CACNB4, CACNG1, CACNG2, CACNG3, CACNG4, CACNG5, CACNG6,CACNG7, CACNG8, CACTIN, CACUL1, CACYBP, CAD, CADM1, CADM2, CADM3, CADM4,CADPS, CADPS2, CAGE1, CALB1, CALB2, CALCA, CALCB, CALCOCO1, CALCOCO2,CALCR, CALCRL, CALD1, CALHM1, CALHM2, CALHM3, CALM1, CALM2, CALM3,CALML3, CALML4, CALML5, CALML6, CALN1, CALR, CALR3, CALU, CALY, CAMK1,CAMK1D, CAMK1G, CAMK2A, CAMK2B, CAMK2D, CAMK2G, CAMK2N1, CAMK2N2, CAMK4,CAMKK1, CAMKK2, CAMKMT, CAMKV, CAMLG, CAMP, CAMSAP1, CAMSAP2, CAMSAP3,CAMTA1, CAMTA2, CAND1, CAND2, CANT1, CANX, CAP1, CAP2, CAPG, CAPN1,CAPN10, CAPN11, CAPN12, CAPN13, CAPN14, CAPN15, CAPN2, CAPN3, CAPN5,CAPN6, CAPN7, CAPN8, CAPN9, CAPNS1, CAPNS2, CAPRIN1, CAPRIN2, CAPS,CAPS2, CAPSL, CAPZA1, CAPZA2, CAPZA3, CAPZB, CARD10, CARD11, CARD14,CARD16, CARD17, CARD18, CARD19, CARD6, CARDS, CARDS, CARF, CARHSP1,CARM1, CARMIL1, CARMIL2, CARMIL3, CARNMT1, CARNS1, CARS, CARS2, CARTPT,CASC1, CASC10, CASC3, CASC4, CASD1, CASK, CASKIN1, CASKIN2, CASP1,CASP10, CASP12, CASP14, CASP2, CASP3, CASP4, CASP5, CASP6, CASP7, CASP8,CASP8AP2, CASP9, CASQ1, CASQ2, CASR, CASS4, CAST, CASTOR1, CASTOR2,CASZ1, CAT, CATIP, CATSPER1, CATSPER2, CATSPER3, CATSPER4, CATSPERB,CATSPERD, CATSPERE, CATSPERG, CATSPERZ, CAV1, CAV2, CAV3, CAVIN1,CAVIN2, CAVIN3, CAVIN4, CBARP, CBFA2T2, CBFA2T3, CBFB, CBL, CBLB, CBLC,CBLL1, CBLN1, CBLN2, CBLN3, CBLN4, CBR1, CBR3, CBR4, CBS, CBSL, CBWD1,CBWD2, CBWD3, CBWD5, CBWD6, CBX1, CBX2, CBX3, CBX4, CBX5, CBX6, CBX7,CBX8, CBY1, CBY3, CC2D1A, CC2D1B, CC2D2A, CC2D2B, CCAR1, CCAR2, CCBE1,CCDC102A, CCDC102B, CCDC103, CCDC105, CCDC106, CCDC107, CCDC110,CCDC112, CCDC113, CCDC114, CCDC115, CCDC116, CCDC117, CCDC12, CCDC120,CCDC121, CCDC122, CCDC124, CCDC125, CCDC126, CCDC127, CCDC129, CCDC13,CCDC130, CCDC134, CCDC136, CCDC137, CCDC138, CCDC14, CCDC140, CCDC141,CCDC142, CCDC144A, CCDC144NL, CCDC146, CCDC148, CCDC149, CCDC15,CCDC150, CCDC151, CCDC152, CCDC153, CCDC154, CCDC155, CCDC157, CCDC158,CCDC159, CCDC160, CCDC163, CCDC166, CCDC167, CCDC168, CCDC169,CCDC169-SOHLH2, CCDC17, CCDC170, CCDC171, CCDC172, CCDC173, CCDC174,CCDC175, CCDC177, CCDC178, CCDC179, CCDC18, CCDC180, CCDC181, CCDC182,CCDC183, CCDC184, CCDC185, CCDC186, CCDC187, CCDC188, CCDC189, CCDC190,CCDC191, CCDC192, CCDC194, CCDC195, CCDC196, CCDC197, CCDC22, CCDC24,CCDC25, CCDC27, CCDC28A, CCDC28B, CCDC3, CCDC30, CCDC32, CCDC33, CCDC34,CCDC36, CCDC38, CCDC39, CCDC40, CCDC42, CCDC43, CCDC47, CCDC50, CCDC51,CCDC54, CCDC57, CCDC58, CCDC59, CCDC6, CCDC60, CCDC61, CCDC62, CCDC63,CCDC65, CCDC66, CCDC68, CCDC69, CCDC7, CCDC70, CCDC71, CCDC71L, CCDC73,CCDC74A, CCDC74B, CCDC77, CCDC78, CCDC8, CCDC80, CCDC81, CCDC82, CCDC83,CCDC84, CCDC85A, CCDC85B, CCDC85C, CCDC86, CCDC87, CCDC88A, CCDC88B,CCDC88C, CCDC89, CCDC9, CCDC90B, CCDC91, CCDC92, CCDC93, CCDC94, CCDC96,CCDC97, CCER1, CCER2, CCHCR1, CCIN, CCK, CCKAR, CCKBR, CCL1, CCL11,CCL13, CCL14, CCL15, CCL15-CCL14, CCL16, CCL17, CCL18, CCL19, CCL2,CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3,CCL3L1, CCL3L3, CCL4, CCL4L2, CCL5, CCL7, CCL8, CCM2, CCM2L, CCNA1,CCNA2, CCNB1, CCNBlIP1, CCNB2, CCNB3, CCNC, CCND1, CCND2, CCND3,CCNDBP1, CCNE1, CCNE2, CCNF, CCNG1, CCNG2, CCNH, CCNI, CCNI2, CCNJ,CCNJL, CCNK, CCNL1, CCNL2, CCNO, CCNT1, CCNT2, CCNY, CCNYL1, CCP110,CCPG1, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9,CCRL2, CCS, CCSAP, CCSER1, CCSER2, CCT2, CCT3, CCT4, CCT5, CCT6A, CCT6B,CCT7, CCT8, CCT8L2, CCZ1, CCZ1B, CD101, CD109, CD14, CD151, CD160,CD163, CD163L1, CD164, CD164L2, CD177, CD180, CD19, CD1A, CD1B, CD1C,CD1D, CD1E, CD2, CD200, CD200R1, CD200R1L, CD207, CD209, CD22, CD226,CD24, CD244, CD247, CD248, CD27, CD274, CD276, CD28, CD2AP, CD2BP2,CD300A, CD300C, CD300E, CD300LB, CD300LD, CD300LF, CD300LG, CD302,CD320, CD33, CD34, CD36, CD37, CD38, CD3D, CD3E, CD3EAP, CD3G, CD4,CD40, CD40LG, CD44, CD46, CD47, CD48, CD5, CD52, CD53, CD55, CD58, CD59,CD5L, CD6, CD63, CD68, CD69, CD7, CD70, CD72, CD74, CD79A, CD79B, CD80,CD81, CD82, CD83, CD84, CD86, CD8A, CD8B, CD9, CD93, CD96, CD99, CD99L2,CDA, CDADC1, CDAN1, CDC123, CDC14A, CDC14B, CDC16, CDC20, CDC20B, CDC23,CDC25A, CDC25B, CDC25C, CDC26, CDC27, CDC34, CDC37, CDC37L1, CDC40,CDC42, CDC42BPA, CDC42BPB, CDC42BPG, CDC42EP1, CDC42EP2, CDC42EP3,CDC42EP4, CDC42EP5, CDC42SE1, CDC42SE2, CDC45, CDC5L, CDC6, CDC7, CDC73,CDCA2, CDCA3, CDCA4, CDCA5, CDCA7, CDCA7L, CDCA8, CDCP1, CDCP2, CDH1,CDH10, CDH11, CDH12, CDH13, CDH15, CDH16, CDH17, CDH18, CDH19, CDH2,CDH20, CDH22, CDH23, CDH24, CDH26, CDH3, CDH4, CDH5, CDH6, CDH7, CDH8,CDH9, CDHR1, CDHR2, CDHR3, CDHR4, CDHR5, CDIP1, CDIPT, CDK1, CDK10,CDK11A, CDK11B, CDK12, CDK13, CDK14, CDK15, CDK16, CDK17, CDK18, CDK19,CDK2, CDK20, CDK2AP1, CDK2AP2, CDK3, CDK4, CDK5, CDK5R1, CDK5R2,CDK5RAP1, CDK5RAP2, CDK5RAP3, CDK6, CDK7, CDK8, CDK9, CDKAL1, CDKL1,CDKL2, CDKL3, CDKL4, CDKL5, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2AIP,CDKN2AIPNL, CDKN2B, CDKN2C, CDKN2D, CDKN3, CDNF, CDO1, CDON, CDPF1,CDR1, CDR2, CDR2L, CDRT1, CDRT15, CDRT15L2, CDRT4, CDS1, CDS2, CDSN,CDT1, CDV3, CDX1, CDX2, CDX4, CDY1, CDY1B, CDY2A, CDY2B, CDYL, CDYL2,CEACAM1, CEACAM16, CEACAM19, CEACAM20, CEACAM21, CEACAM3, CEACAM4,CEACAM5, CEACAM6, CEACAM7, CEACAM8, CEBPA, CEBPB, CEBPD, CEBPE, CEBPG,CEBPZ, CEBPZOS, CECR2, CEL, CELA1, CELA2A, CELA2B, CELA3A, CELA3B,CELF1, CELF2, CELF3, CELF4, CELF5, CELF6, CELSR1, CELSR2, CELSR3, CEMIP,CEMP1, CEND1, CENPA, CENPB, CENPBD1, CENPC, CENPE, CENPF, CENPH, CENPI,CENPJ, CENPK, CENPL, CENPM, CENPN, CENPO, CENPP, CENPQ, CENPS,CENPS-CORT, CENPT, CENPU, CENPV, CENPVL1, CENPVL2, CENPVL3, CENPW,CENPX, CEP104, CEP112, CEP120, CEP126, CEP128, CEP131, CEP135, CEP152,CEP162, CEP164, CEP170, CEP170B, CEP19, CEP192, CEP250, CEP290, CEP295,CEP295NL, CEP350, CEP41, CEP44, CEP55, CEP57, CEP57L1, CEP63, CEP68,CEP70, CEP72, CEP76, CEP78, CEP83, CEP85, CEP85L, CEP89, CEP95, CEP97,CEPT1, CER1, CERCAM, CERK, CERKL, CERS1, CERS2, CERS3, CERS4, CERS5,CERS6, CES1, CES2, CES3, CES4A, CES5A, CETN1, CETN2, CETN3, CETP,CFAP100, CFAP126, CFAP157, CFAP161, CFAP20, CFAP206, CFAP221, CFAP36,CFAP43, CFAP44, CFAP45, CFAP46, CFAP47, CFAP52, CFAP53, CFAP54, CFAP57,CFAP58, CFAP61, CFAP65, CFAP69, CFAP70, CFAP73, CFAP74, CFAP77, CFAP97,CFAP99, CFB, CFC1, CFC1B, CFD, CFDP1, CFH, CFHR1, CFHR2, CFHR3, CFHR4,CFHR5, CFI, CFL1, CFL2, CFLAR, CFP, CFTR, CGA, CGB1, CGB2, CGB3, CGB5,CGB7, CGB8, CGGBP1, CGN, CGNL1, CGREF1, CGRRF1, CH25H, CHAC1, CHAC2,CHAD, CHADL, CHAF1A, CHAF1B, CHAMP1, CHAT, CHCHD1, CHCHD10, CHCHD2,CHCHD3, CHCHD4, CHCHD5, CHCHD6, CHCHD7, CHD1, CHD1L, CHD2, CHD3, CHD4,CHD5, CHD6, CHD7, CHD8, CHD9, CHDH, CHEK1, CHEK2, CHERP, CHFR, CHGA,CHGB, CHI3L1, CHI3L2, CHIA, CHIC1, CHIC2, CHID1, CHIT1, CHKA, CHKB,CHKB-CPT1B, CHL1, CHM, CHML, CHMP1A, CHMP1B, CHMP2A, CHMP2B, CHMP3,CHMP4A, CHMP4B, CHMP4C, CHMP5, CHMP6, CHMP7, CHN1, CHN2, CHODL, CHORDC1,CHP1, CHP2, CHPF, CHPF2, CHPT1, CHRAC1, CHRD, CHRDL1, CHRDL2, CHRFAM7A,CHRM1, CHRM2, CHRM3, CHRM4, CHRM5, CHRNA1, CHRNA10, CHRNA2, CHRNA3,CHRNA4, CHRNA5, CHRNA6, CHRNA7, CHRNA9, CHRNB1, CHRNB2, CHRNB3, CHRNB4,CHRND, CHRNE, CHRNG, CHST1, CHST10, CHST11, CHST12, CHST13, CHST14,CHST15, CHST2, CHST3, CHST4, CHST5, CHST6, CHST7, CHST8, CHST9, CHSY1,CHSY3, CHTF18, CHTF8, CHTOP, CHUK, CHURC1, CHURC1-FNTB, CIAO1, CIAPIN1,CIART, CIB1, CIB2, CIB3, CIB4, CIC, CIDEA, CIDEB, CIDEC, CIITA, CILP,CILP2, CINP, CIPC, CIR1, CIRBP, CISD1, CISD2, CISD3, CISH, CIT, CITED1,CITED2, CITED4, CIZ1, CKAP2, CKAP2L, CKAP4, CKAP5, CKB, CKLF,CKLF-CMTM1, CKM, CKMT1A, CKMT1B, CKMT2, CKS1B, CKS2, CLASP1, CLASP2,CLASRP, CLC, CLCA1, CLCA2, CLCA4, CLCC1, CLCF1, CLCN1, CLCN2, CLCN3,CLCN4, CLCN5, CLCN6, CLCN7, CLCNKA, CLCNKB, CLDN1, CLDN10, CLDN11,CLDN12, CLDN14, CLDN15, CLDN16, CLDN17, CLDN18, CLDN19, CLDN2, CLDN20,CLDN22, CLDN23, CLDN24, CLDN25, CLDN3, CLDN34, CLDN4, CLDN5, CLDN6,CLDN7, CLDN8, CLDN9, CLDND1, CLDND2, CLEC10A, CLEC11A, CLEC12A, CLEC12B,CLEC14A, CLEC 16A, CLEC17A, CLEC18A, CLEC18B, CLEC18C, CLEC19A, CLEC1A,CLEC1B, CLEC20A, CLEC2A, CLEC2B, CLEC2D, CLEC2L, CLEC3A, CLEC3B, CLEC4A,CLEC4C, CLEC4D, CLEC4E, CLEC4F, CLEC4G, CLEC4M, CLEC5A, CLEC6A, CLEC7A,CLEC9A, CLECL1, CLGN, CLHC1, CLIC1, CLIC2, CLIC3, CLIC4, CLIC5, CLIC6,CLINT1, CLIP1, CLIP2, CLIP3, CLIP4, CLK1, CLK2, CLK3, CLK4, CLLU1,CLLU10S, CLMN, CLMP, CLN3, CLN5, CLN6, CLN8, CLNK, CLNS1A, CLOCK, CLP1,CLPB, CLPP, CLPS, CLPSL1, CLPSL2, CLPTM1, CLPTM1L, CLPX, CLRN1, CLRN2,CLRN3, CLSPN, CLSTN1, CLSTN2, CLSTN3, CLTA, CLTB, CLTC, CLTCL1, CLU,CLUAP1, CLUH, CLUL1, CLVS1, CLVS2, CLYBL, CMA1, CMAS, CMBL, CMC1, CMC2,CMC4, CMIP, CMKLR1, CMPK1, CMPK2, CMSS1, CMTM1, CMTM2, CMTM3, CMTM4,CMTM5, CMTM6, CMTM7, CMTM8, CMTR1, CMTR2, CMYA5, CNBD1, CNBD2, CNBP,CNDP1, CNDP2, CNEP1R1, CNFN, CNGA1, CNGA2, CNGA3, CNGA4, CNGB1, CNGB3,CNIH1, CNIH2, CNIH3, CNIH4, CNKSR1, CNKSR2, CNKSR3, CNMD, CNN1, CNN2,CNN3, CNNM1, CNNM2, CNNM3, CNNM4, CNOT1, CNOT10, CNOT11, CNOT2, CNOT3,CNOT4, CNOT6, CNOT6L, CNOT7, CNOT8, CNOT9, CNP, CNPPD1, CNPY1, CNPY2,CNPY3, CNPY4, CNR1, CNR2, CNRIP1, CNST, CNTD1, CNTD2, CNTF, CNTFR,CNTLN, CNTN1, CNTN2, CNTN3, CNTN4, CNTN5, CNTN6, CNTNAP1, CNTNAP2,CNTNAP3, CNTNAP3B, CNTNAP4, CNTNAP5, CNTRL, CNTROB, COA1, COA3, COA4,COA5, COA6, COA7, COASY, COBL, COBLL1, COCH, COG1, COG2, COG3, COG4,COG5, COG6, COG7, COG8, COIL, COL10A1, COL11A1, COL11A2, COL12A1,COL13A1, COL14A1, COL15A1, COL16A1, COL17A1, COL18A1, COL19A1, COL1A1,COL1A2, COL20A1, COL21A1, COL22A1, COL23A1, COL24A1, COL25A1, COL26A1,COL27A1, COL28A1, COL2A1, COL3A1, COL4A1, COL4A2, COL4A3, COL4A3BP,COL4A4, COL4A5, COL4A6, COL5A1, COL5A2, COL5A3, COL6A1, COL6A2, COL6A3,COL6A5, COL6A6, COL7A1, COL8A1, COL8A2, COL9A1, COL9A2, COL9A3, COLCA2,COLEC10, COLEC11, COLEC12, COLGALT1, COLGALT2, COLQ, COMMD1, COMMD10,COMMD2, COMMD3, COMMD3-BMI1, COMMD4, COMMD5, COMMD6, COMMD7, COMMD8,COMMD9, COMP, COMT, COMTD1, COPA, COPB1, COPB2, COPE, COPG1, COPG2,COPRS, COPS2, COPS3, COPS4, COPS5, COPS6, COPS7A, COPS7B, COPS8, COPS9,COPZ1, COPZ2, COQ10A, COQ10B, COQ2, COQ3, COQ4, COQ5, COQ6, COQ7, COQ8A,COQ8B, COQ9, CORIN, CORO1A, CORO1B, CORO1C, CORO2A, CORO2B, CORO6,CORO7, CORO7-PAM16, CORT, COTL1, COX10, COX11, COX14, COX15, COX16,COX17, COX18, COX19, COX20, COX4I1, COX4I2, COX5A, COX5B, COX6A1,COX6A2, COX6B1, COX6B2, COX6C, COX7A1, COX7A2, COX7A2L, COX7B, COX7B2,COX7C, COX8A, COX8C, CP, CPA1, CPA2, CPA3, CPA4, CPA5, CPA6, CPAMD8,CPB1, CPB2, CPD, CPE, CPEB1, CPEB2, CPEB3, CPEB4, CPED1, CPLX1, CPLX2,CPLX3, CPLX4, CPM, CPN1, CPN2, CPNE1, CPNE2, CPNE3, CPNE4, CPNE5, CPNE6,CPNE7, CPNE8, CPNE9, CPO, CPDX, CPPED1, CPQ, CPS1, CPSF1, CPSF2, CPSF3,CPSF4, CPSF4L, CPSF6, CPSF7, CPT1A, CPT1B, CPT1C, CPT2, CPTP, CPVL,CPXCR1, CPXM1, CPXM2, CPZ, CR1, CR1L, CR2, CR354443.1, CR354443.2,CR388407.3, CR547123.3, CR753842.1, CR753845.2, CR759815.2, CR788250.1,CR847794.2, CR854858.1, CR933783.3, CR936239.1, CRABP1, CRABP2, CRACR2A,CRACR2B, CRADD, CRAMP1, CRAT, CRB1, CRB2, CRB3, CRBN, CRCP, CRCT1,CREB1, CREB3, CREB3L1, CREB3L2, CREB3L3, CREB3L4, CREB5, CREBBP, CREBL2,CREBRF, CREBZF, CREG1, CREG2, CRELD1, CRELD2, CREM, CRH, CRHBP, CRHR1,CRHR2, CRIM1, CRIP1, CRIP2, CRIP3, CRIPT, CRISP1, CRISP2, CRISP3,CRISPLD1, CRISPLD2, CRK, CRKL, CRLF1, CRLF2, CRLF3, CRLS1, CRMP1,CRNKL1, CRNN, CROCC, CROCC2, CROT, CRP, CRTAC1, CRTAM, CRTAP, CRTC1,CRTC2, CRTC3, CRX, CRY1, CRY2, CRYAA, CRYAB, CRYBA1, CRYBA2, CRYBA4,CRYBB1, CRYBB2, CRYBB3, CRYBG1, CRYBG2, CRYBG3, CRYGA, CRYGB, CRYGC,CRYGD, CRYGN, CRYGS, CRYL1, CRYM, CRYZ, CRYZL1, CS, CSAD, CSAG1, CSAG2,CSAG3, CSDC2, CSDE1, CSE1L, CSF1, CSF1R, CSF2, CSF2RA, CSF2RB, CSF3,CSF3R, CSGALNACT1, CSGALNACT2, CSH1, CSH2, CSHL1, CSK, CSMD1, CSMD2,CSMD3, CSN1S1, CSN2, CSN3, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E, CSNK1G1,CSNK1G2, CSNK1G3, CSNK2A1, CSNK2A2, CSNK2A3, CSNK2B, CSPG4, CSPG5,CSPP1, CSRNP1, CSRNP2, CSRNP3, CSRP1, CSRP2, CSRP3, CST1, CST11, CST2,CST3, CST4, CST5, CST6, CST7, CST8, CST9, CST9L, CSTA, CSTB, CSTF1,CSTF2, CSTF2T, CSTF3, CSTL1, CT45A1, CT45A10, CT45A2, CT45A3, CT45A5,CT45A6, CT45A7, CT45A8, CT45A9, CT476828.1, CT476828.10, CT476828.11,CT476828.12, CT476828.13, CT476828.14, CT476828.15, CT476828.16,CT476828.17, CT476828.18, CT476828.19, CT476828.2, CT476828.20,CT476828.21, CT476828.22, CT476828.3, CT476828.4, CT476828.5,CT476828.6, CT476828.7, CT476828.8, CT476828.9, CT47A1, CT47A10,CT47A11, CT47A12, CT47A2, CT47A3, CT47A4, CT47A5, CT47A6, CT47A7,CT47A8, CT47A9, CT47B1, CT55, CT62, CT83, CTAG1A, CTAG1B, CTAG2, CTAGE1,CTAGE15, CTAGE4, CTAGE5, CTAGE6, CTAGE8, CTAGE9, CTBP1, CTBP2, CTBS,CTC1, CTCF, CTCFL, CTDNEP1, CTDP1, CTDSP1, CTDSP2, CTDSPL, CTDSPL2,CTF1, CTGF, CTH, CTHRC1, CTIF, CTLA4, CTNNA1, CTNNA2, CTNNA3, CTNNAL1,CTNNB1, CTNNBIP1, CTNNBL1, CTNND1, CTNND2, CTNS, CTPS1, CTPS2, CTR9,CTRB1, CTRB2, CTRC, CTRL, CTSA, CTSB, CTSC, CTSD, CTSE, CTSF, CTSG,CTSH, CTSK, CTSL, CTSO, CTSS, CTSV, CTSW, CTSZ, CTTN, CTTNBP2,CTTNBP2NL, CTU1, CTU2, CTXN1, CTXN2, CTXN3, CTXND1, CU464060.1,CU633846.1, CU633980.1, CU633980.2, CU639417.1, CU639417.2, CUBN,CUEDC1, CUEDC2, CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5, CUL7, CUL9, CUTA,CUTC, CUX1, CUX2, CUZD1, CWC15, CWC22, CWC25, CWC27, CWF19L1, CWF19L2,CWH43, CX3CL1, CX3CR1, CXADR, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13,CXCL14, CXCL16, CXCL17, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, CXCL9, CXCR1,CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXorf21, CXorf36, CXorf38, CXorf40A,CXorf40B, CXorf49, CXorf49B, CXorf51A, CXorf51B, CXorf56, CXorf57,CXorf58, CXorf65, CXorf66, CXorf67, CXXC1, CXXC4, CXXC5, CYB561,CYB561A3, CYB561D1, CYB561D2, CYB5A, CYB5B, CYB5D1, CYB5D2, CYB5R1,CYB5R2, CYB5R3, CYB5R4, CYB5RL, CYBA, CYBB, CYBRD1, CYC1, CYCS, CYFIP1,CYFIP2, CYGB, CYHR1, CYLC1, CYLC2, CYLD, CYP11A1, CYP11B1, CYP11B2,CYP17A1, CYP19A1, CYP1A1, CYP1A2, CYP1B1, CYP20A1, CYP21A2, CYP24A1,CYP26A1, CYP26B1, CYP26C1, CYP27A1, CYP27B1, CYP27C1, CYP2A13, CYP2A6,CYP2A7, CYP2B6, CYP2C18, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2D7,CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1, CYP39A1, CYP3A4,CYP3A43, CYP3A5, CYP3A7, CYP3A7-CYP3A51P, CYP46A1, CYP4A11, CYP4A22,CYP4B1, CYP4F11, CYP4F12, CYP4F2, CYP4F22, CYP4F3, CYP4F8, CYP4V2,CYP4X1, CYP4Z1, CYP51A1, CYP7A1, CYP7B1, CYP8B1, CYR61, CYS1, CYSLTR1,CYSLTR2, CYSRT1, CYSTM1, CYTH1, CYTH2, CYTH3, CYTH4, CYTIP, CYTL1,CYYR1, D2HGDH, DAAM1, DAAM2, DAB1, DAB2, DAB2IP, DACH1, DACH2, DACT1,DACT2, DACT3, DAD1, DAG1, DAGLA, DAGLB, DALRD3, DAND5, DAO, DAOA, DAP,DAP3, DAPK1, DAPK2, DAPK3, DAPL1, DAPP1, DARS, DARS2, DAW1, DAXX, DAZ1,DAZ2, DAZ3, DAZ4, DAZAP1, DAZAP2, DAZL, DBF4, DBF4B, DBH, DBI, DBN1,DBNDD1, DBNDD2, DBNL, DBP, DBR1, DBT, DBX1, DBX2, DCAF1, DCAF10, DCAF11,DCAF12, DCAF12L1, DCAF12L2, DCAF13, DCAF15, DCAF16, DCAF17, DCAF4,DCAF4L1, DCAF4L2, DCAF5, DCAF6, DCAF7, DCAF8, DCAF8L1, DCAF8L2, DCAKD,DCANP1, DCBLD1, DCBLD2, DCC, DCD, DCDC1, DCDC2, DCDC2B, DCDC2C, DCHS1,DCHS2, DCK, DCLK1, DCLK2, DCLK3, DCLRE1A, DCLRE1B, DCLRE1C, DCN, DCP1A,DCP1B, DCP2, DCPS, DCST1, DCST2, DCSTAMP, DCT, DCTD, DCTN1, DCTN2,DCTN3, DCTN4, DCTN5, DCTN6, DCTPP1, DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4,DCUN1D5, DCX, DCXR, DDA1, DDAH1, DDAH2, DDB1, DDB2, DDC, DDHD1, DDHD2,DDI1, DDI2, DDIAS, DDIT3, DDIT4, DDIT4L, DDN, DDO, DDOST, DDR1, DDR2,DDRGK1, DDT, DDTL, DDX1, DDX10, DDX11, DDX17, DDX18, DDX19A, DDX19B,DDX20, DDX21, DDX23, DDX24, DDX25, DDX27, DDX28, DDX31, DDX39A, DDX39B,DDX3X, DDX3Y, DDX4, DDX41, DDX42, DDX43, DDX46, DDX47, DDX49, DDX5,DDX50, DDX51, DDX52, DDX53, DDX54, DDX55, DDX56, DDX58, DDX59, DDX6,DDX60, DDX60L, DEAF1, DEC1, DECR1, DECR2, DEDD, DEDD2, DEF6, DEF8,DEFA1, DEFA1B, DEFA3, DEFA4, DEFA5, DEFA6, DEFB1, DEFB103A, DEFB103B,DEFB104A, DEFB104B, DEFB105A, DEFB105B, DEFB106A, DEFB106B, DEFB107A,DEFB107B, DEFB108B, DEFB110, DEFB112, DEFB113, DEFB114, DEFB115,DEFB116, DEFB118, DEFB119, DEFB121, DEFB123, DEFB124, DEFB125, DEFB126,DEFB127, DEFB128, DEFB129, DEFB130A, DEFB130B, DEFB131A, DEFB131B,DEFB132, DEFB133, DEFB134, DEFB135, DEFB136, DEFB4A, DEFB4B, DEGS1,DEGS2, DEK, DENND1A, DENND1B, DENND1C, DENND2A, DENND2C, DENND2D,DENND3, DENND4A, DENND4B, DENND4C, DENND5A, DENND5B, DENND6A, DENND6B,DENR, DEPDC1, DEPDC1B, DEPDC4, DEPDC5, DEPDC7, DEPTOR, DERA, DERL1,DERL2, DERL3, DES, DESI1, DESI2, DET1, DEUP1, DEXI, DFFA, DFFB, DFNA5,DFNB59, DGAT1, DGAT2, DGAT2L6, DGCR2, DGCR6, DGCR6L, DGCR8, DGKA, DGKB,DGKD, DGKE, DGKG, DGKH, DGKI, DGKK, DGKQ, DGKZ, DGUOK, DHCR24, DHCR7,DHDDS, DHDH, DHFR, DHFR2, DHH, DHODH, DHPS, DHRS1, DHRS11, DHRS12,DHRS13, DHRS2, DHRS3, DHRS4, DHRS4L2, DHRS7, DHRS7B, DHRS7C, DHRS9,DHRSX, DHTKD1, DHX15, DHX16, DHX29, DHX30, DHX32, DHX33, DHX34, DHX35,DHX36, DHX37, DHX38, DHX40, DHX57, DHX58, DHX8, DHX9, DIABLO, DIAPH1,DIAPH2, DIAPH3, DICER1, DIDO1, DIEXF, DIMT1, DIO1, DIO2, DIO3, DIP2A,DIP2B, DIP2C, DIRAS1, DIRAS2, DIRAS3, DIRC1, DIRC2, DIRC3, DIS3, DIS3L,DIS3L2, DISC1, DISP1, DISP2, DISP3, DIXDC1, DKC1, DKK1, DKK2, DKK3,DKK4, DKKL1, DLAT, DLC1, DLD, DLEC1, DLEU7, DLG1, DLG2, DLG3, DLG4,DLG5, DLGAP1, DLGAP2, DLGAP3, DLGAP4, DLGAP5, DLK1, DLK2, DLL1, DLL3,DLL4, DLST, DLX1, DLX2, DLX3, DLX4, DLX5, DLX6, DMAC1, DMAC2, DMAP1,DMBT1, DMBX1, DMC1, DMD, DMGDH, DMKN, DMP1, DMPK, DMRT1, DMRT2, DMRT3,DMRTA1, DMRTA2, DMRTB1, DMRTC1, DMRTC1B, DMRTC2, DMTF1, DMTN, DMWD,DMXL1, DMXL2, DNA2, DNAAF1, DNAAF2, DNAAF3, DNAAF4, DNAAF5, DNAH1,DNAH10, DNAH100S, DNAH11, DNAH12, DNAH14, DNAH17, DNAH2, DNAH3, DNAH5,DNAH6, DNAH7, DNAH8, DNAH9, DNAI1, DNAI2, DNAJA1, DNAJA2, DNAJA3,DNAJA4, DNAJB1, DNAJB11, DNAJB12, DNAJB13, DNAJB14, DNAJB2, DNAJB4,DNAJB5, DNAJB6, DNAJB7, DNAJB8, DNAJB9, DNAJC1, DNAJC10, DNAJC11,DNAJC12, DNAJC13, DNAJC14, DNAJC15, DNAJC16, DNAJC17, DNAJC18, DNAJC19,DNAJC2, DNAJC21, DNAJC22, DNAJC24, DNAJC25, DNAJC25-GNG10, DNAJC27,DNAJC28, DNAJC3, DNAJC30, DNAJC4, DNAJC5, DNAJC5B, DNAJC5G, DNAJC6,DNAJC7, DNAJC8, DNAJC9, DNAL1, DNAL4, DNALI1, DNASE1, DNASE1L1,DNASE1L2, DNASE1L3, DNASE2, DNASE2B, DND1, DNER, DNHD1, DNLZ, DNM1,DNM1L, DNM2, DNM3, DNMBP, DNMT1, DNMT3A, DNMT3B, DNMT3L, DNPEP, DNPH1,DNTT, DNTTIP1, DNTTIP2, DOC2A, DOC2B, DOCK1, DOCK10, DOCK11, DOCK2,DOCK3, DOCK4, DOCK5, DOCK6, DOCK7, DOCK8, DOCK9, DOHH, DOK1, DOK2, DOK3,DOK4, DOK5, DOK6, DOK7, DOLK, DOLPP1, DONSON, DOPEY1, DOPEY2, DOT1L,DPAGT1, DPCD, DPCR1, DPEP1, DPEP2, DPEP3, DPF1, DPF2, DPF3, DPH1, DPH2,DPH3, DPH5, DPH6, DPH7, DPM1, DPM2, DPM3, DPP10, DPP3, DPP4, DPP6, DPP7,DPP8, DPP9, DPPA2, DPPA3, DPPA4, DPPA5, DPRX, DPT, DPY19L1, DPY19L2,DPY19L3, DPY19L4, DPY30, DPYD, DPYS, DPYSL2, DPYSL3, DPYSL4, DPYSL5,DQX1, DR1, DRAM1, DRAM2, DRAP1, DRAXIN, DRC1, DRC3, DRC7, DRD1, DRD2,DRD3, DRD4, DRD5, DRG1, DRG2, DRGX, DRICH1, DROSHA, DRP2, DSC1, DSC2,DSC3, DSCAM, DSCAML1, DSCC1, DSCR3, DSCR4, DSCR8, DSE, DSEL, DSG1, DSG2,DSG3, DSG4, DSN1, DSP, DSPP, DST, DSTN, DSTYK, DTD1, DTD2, DTHD1, DTL,DTNA, DTNB, DTNBP1, DTWD1, DTWD2, DTX1, DTX2, DTX3, DTX3L, DTX4, DTYMK,DUOX1, DUOX2, DUOXA1, DUOXA2, DUPD1, DUS1L, DUS2, DUS3L, DUS4L, DUSP1,DUSP10, DUSP11, DUSP12, DUSP13, DUSP14, DUSP15, DUSP16, DUSP18, DUSP19,DUSP2, DUSP21, DUSP22, DUSP23, DUSP26, DUSP27, DUSP28, DUSP3, DUSP4,DUSP5, DUSP6, DUSP7, DUSP8, DUSP9, DUT, DUX4, DUXA, DUXB, DVL1, DVL2,DVL3, DWORF, DXO, DYDC1, DYDC2, DYM, DYNAP, DYNC1H1, DYNC1I1, DYNC1I2,DYNC1LI1, DYNC1LI2, DYNC2H1, DYNC2LI1, DYNLL1, DYNLL2, DYNLRB1, DYNLRB2,DYNLT1, DYNLT3, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, DYSF, DYTN, DZANK1,DZIP1, DZIP1L, DZIP3, E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7, E2F8,E4F1, EAF1, EAF2, EAPP, EARS2, EBAG9, EBF1, EBF2, EBF3, EBF4, EBI3,EBLN1, EBLN2, EBNA1BP2, EBP, EBPL, ECD, ECE1, ECE2, ECEL1, ECH1, ECHDC1,ECHDC2, ECHDC3, ECHS1, ECI1, ECI2, ECM1, ECM2, ECSCR, ECSIT, ECT2,ECT2L, EDA, EDA2R, EDAR, EDARADD, EDC3, EDC4, EDDM13, EDDM3A, EDDM3B,EDEM1, EDEM2, EDEM3, EDF1, EDIL3, EDN1, EDN2, EDN3, EDNRA, EDNRB, EDRF1,EEA1, EED, EEF1A1, EEF1A2, EEF1AKMT1, EEF1AKMT2, EEF1AKMT3, EEF1B2,EEF1D, EEF1E1, EEF1E1-BLOC1S5, EEF1G, EEF2, EEF2K, EEF2KMT, EEFSEC,EEPD1, EFCAB1, EFCAB10, EFCAB11, EFCAB12, EFCAB13, EFCAB14, EFCAB2,EFCAB3, EFCAB5, EFCAB6, EFCAB7, EFCAB8, EFCAB9, EFCC1, EFEMP1, EFEMP2,EFHB, EFHC1, EFHC2, EFHD1, EFHD2, EFL1, EFNA1, EFNA2, EFNA3, EFNA4,EFNA5, EFNB1, EFNB2, EFNB3, EFR3A, EFR3B, EFS, EFTUD2, EGF, EGFL6,EGFL7, EGFL8, EGFLAM, EGFR, EGLN1, EGLN2, EGLN3, EGR1, EGR2, EGR3, EGR4,EHBP1, EHBP1L1, EHD1, EHD2, EHD3, EHD4, EHF, EHHADH, EHMT1, EHMT2, EI24,EID1, EID2, EID2B, EID3, EIF1, EIF1AD, EIF1AX, EIF1AY, EIF1B, EIF2A,EIF2AK1, EIF2AK2, EIF2AK3, EIF2AK4, EIF2B1, EIF2B2, EIF2B3, EIF2B4,EIF2B5, EIF2D, EIF2S1, EIF2S2, EIF2S3, EIF3A, EIF3B, EIF3C, EIF3CL,EIF3D, EIF3E, EIF3F, EIF3G, EIF3H, EIF3I, EIF3J, EIF3K, EIF3L, EIF3M,EIF4A1, EIF4A2, EIF4A3, EIF4B, EIF4E, EIF4E1B, EIF4E2, EIF4E3, EIF4EBP1,EIF4EBP2, EIF4EBP3, EIF4ENIF1, EIF4G1, EIF4G2, EIF4G3, EIF4H, EIF5,EIF5A, EIF5A2, EIF5AL1, EIF5B, EIF6, EIPR1, ELAC1, ELAC2, ELANE, ELAVL1,ELAVL2, ELAVL3, ELAVL4, ELF1, ELF2, ELF3, ELF4, ELF5, ELFN1, ELFN2,ELK1, ELK3, ELK4, ELL, ELL2, ELL3, ELMO1, ELMO2, ELMO3, ELMOD1, ELMOD2,ELMOD3, ELMSAN1, ELN, ELOA, ELOA2, ELOA3, ELOA3B, ELOA3C, ELOA3D, ELOB,ELOC, ELOF1, ELOVL1, ELOVL2, ELOVL3, ELOVL4, ELOVL5, ELOVL6, ELOVL7,ELP1, ELP2, ELP3, ELP4, ELP5, ELP6, ELSPBP1, EMB, EMC1, EMC10, EMC2,EMC3, EMC4, EMC6, EMC7, EMC8, EMC9, EMCN, EMD, EME1, EME2, EMG1, EMID1,EMILIN1, EMILIN2, EMILIN3, EML1, EML2, EML3, EML4, EML5, EML6, EMP1,EMP2, EMP3, EMSY, EMX1, EMX2, EN1, EN2, ENAH, ENAM, ENC1, ENDOD1, ENDOG,ENDOU, ENDOV, ENG, ENGASE, ENHO, ENKD1, ENKUR, ENO1, ENO2, ENO3, ENO4,ENOPH1, ENOSF1, ENOX1, ENOX2, ENPEP, ENPP1, ENPP2, ENPP3, ENPP4, ENPP5,ENPP6, ENPP7, ENSA, ENTHD1, ENTPD1, ENTPD2, ENTPD3, ENTPD4, ENTPD5,ENTPD6, ENTPD7, ENTPD8, ENY2, EOGT, EOMES, EP300, EP400, EPAS1, EPB41,EPB41L1, EPB41L2, EPB41L3, EPB41L4A, EPB41L4B, EPB41L5, EPB42, EPC1,EPC2, EPCAM, EPDR1, EPG5, EPGN, EPHA1, EPHA10, EPHA2, EPHA3, EPHA4,EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, EPHX1,EPHX2, EPHX3, EPHX4, EPM2A, EPM2AIP1, EPN1, EPN2, EPN3, EPO, EPOP, EPOR,EPPIN, EPPIN-WFDC6, EPPK1, EPRS, EPS15, EPS15L1, EPS8, EPS8L1, EPS8L2,EPS8L3, EPSTI1, EPX, EPYC, EQTN, ERAL1, ERAP1, ERAP2, ERAS, ERBB2,ERBB3, ERBB4, ERBIN, ERC1, ERC2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5,ERCC6, ERCC6L, ERCC6L2, ERCC8, EREG, ERF, ERFE, ERG, ERG28, ERGIC1,ERGIC2, ERGIC3, ERH, ERI1, ERI2, ERI3, ERICH1, ERICH2, ERICH3, ERICH4,ERICH5, ERICH6, ERICH6B, ERLEC1, ERLIN1, ERLIN2, ERMAP, ERMARD, ERMN,ERMP1, ERN1, ERN2, ERO1A, ERO1B, ERP27, ERP29, ERP44, ERRFI1, ERV3-1,ERVFRD-1, ERVMER34-1, ERVV-1, ERVV-2, ERVW-1, ESAM, ESCO1, ESCO2, ESD,ESF1, ESM1, ESPL1, ESPN, ESPNL, ESR1, ESR2, ESRP1, ESRP2, ESRRA, ESRRB,ESRRG, ESS2, ESX1, ESYT1, ESYT2, ESYT3, ETAA1, ETDA, ETDB, ETDC, ETF1,ETFA, ETFB, ETFBKMT, ETFDH, ETFRF1, ETHE1, ETNK1, ETNK2, ETNPPL, ETS1,ETS2, ETV1, ETV2, ETV3, ETV3L, ETV4, ETV5, ETV6, ETV7, EVA1A, EVA1B,EVA1C, EVC, EVC2, EVI2A, EVI2B, EVI5, EVI5L, EVL, EVPL, EVPLL, EVX1,EVX2, EWSR1, EXD1, EXD2, EXD3, EXO1, EXO5, EXOC1, EXOC1L, EXOC2, EXOC3,EXOC3L1, EXOC3L2, EXOC3L4, EXOC4, EX005, EXOC6, EXOC6B, EXOC7, EXOC8,EXOG, EXOSC1, EXOSC10, EXOSC2, EXOSC3, EXOSC4, EXOSC5, EXOSC6, EXOSC7,EXOSC8, EXOSC9, EXPH5, EXT1, EXT2, EXTL1, EXTL2, EXTL3, EYA1, EYA2,EYA3, EYA4, EYS, EZH1, EZH2, EZR, F10, F11, F11R, F12, F13A1, F13B, F2,F2R, F2RL1, F2RL2, F2RL3, F3, F5, F7, F8, F8A1, F8A2, F8A3, F9, FA2H,FAAH, FAAH2, FAAP100, FAAP20, FAAP24, FABP1, FABP12, FABP2, FABP3,FABP4, FABP5, FABP6, FABP7, FABP9, FADD, FADS1, FADS2, FADS3, FADS6,FAF1, FAF2, FAH, FAHD1, FAHD2A, FAHD2B, FAIM, FAIM2, FAM102A, FAM102B,FAM103A1, FAM104A, FAM104B, FAM105A, FAM106A, FAM107A, FAM107B, FAM109A,FAM109B, FAM110A, FAM110B, FAM110C, FAM110D, FAM111A, FAM111B, FAM114A1,FAM114A2, FAM117A, FAM117B, FAM118A, FAM118B, FAM120A, FAM120AOS,FAM120B, FAM120C, FAM122A, FAM122B, FAM122C, FAM124A, FAM124B, FAM126A,FAM126B, FAM129A, FAM129B, FAM129C, FAM131A, FAM131B, FAM131C, FAM133A,FAM133B, FAM135A, FAM135B, FAM136A, FAM13A, FAM13B, FAM13C, FAM149A,FAM149B1, FAM151A, FAM151B, FAM153A, FAM153B, FAM153C, FAM155A, FAM155B,FAM156A, FAM156B, FAM159A, FAM159B, FAM160A1, FAM160A2, FAM160B1,FAM160B2, FAM161A, FAM161B, FAM162A, FAM162B, FAM163A, FAM163B, FAM166A,FAM166B, FAM167A, FAM167B, FAM168A, FAM168B, FAM169A, FAM169B, FAM170A,FAM170B, FAM171A1, FAM171A2, FAM171B, FAM172A, FAM173A, FAM173B,FAM174A, FAM174B, FAM177A1, FAM177B, FAM178B, FAM180A, FAM180B, FAM181A,FAM181B, FAM182B, FAM183A, FAM184A, FAM184B, FAM185A, FAM186A, FAM186B,FAM187A, FAM187B, FAM189A1, FAM189A2, FAM189B, FAM192A, FAM193A,FAM193B, FAM196A, FAM196B, FAM198A, FAM198B, FAM199X, FAM19A1, FAM19A2,FAM19A3, FAM19A4, FAM19A5, FAM200A, FAM200B, FAM204A, FAM205A, FAM205C,FAM206A, FAM207A, FAM208A, FAM208B, FAM209A, FAM209B, FAM20A, FAM20B,FAM20C, FAM210A, FAM210B, FAM212A, FAM212B, FAM213A, FAM213B, FAM214A,FAM214B, FAM216A, FAM216B, FAM217A, FAM217B, FAM218A, FAM219A, FAM219B,FAM220A, FAM221A, FAM221B, FAM222A, FAM222B, FAM227A, FAM227B, FAM228A,FAM228B, FAM229A, FAM229B, FAM230A, FAM231A, FAM231B, FAM231C, FAM231D,FAM234A, FAM234B, FAM236A, FAM236B, FAM236C, FAM236D, FAM237A, FAM237B,FAM240A, FAM240B, FAM24A, FAM24B, FAM25A, FAM25C, FAM25G, FAM26D,FAM26E, FAM26F, FAM32A, FAM35A, FAM3A, FAM3B, FAM3C, FAM3D, FAM43A,FAM43B, FAM45A, FAM46A, FAM46B, FAM46C, FAM46D, FAM47A, FAM47B, FAM47C,FAM47E, FAM47E-STBD1, FAM49A, FAM49B, FAM50A, FAM50B, FAM53A, FAM53B,FAM53C, FAM57A, FAM57B, FAM58A, FAM60A, FAM69A, FAM69B, FAM69C, FAM71A,FAM71B, FAM71C, FAM71D, FAM71E1, FAM71E2, FAM71F1, FAM71F2, FAM72A,FAM72B, FAM72C, FAM72D, FAM76A, FAM76B, FAM78A, FAM78B, FAM81A, FAM81B,FAM83A, FAM83B, FAM83C, FAM83D, FAM83E, FAM83F, FAM83G, FAM83H, FAM84A,FAM84B, FAM86B1, FAM86B2, FAM86C1, FAM89A, FAM89B, FAM8A1, FAM90A1,FAM90A26, FAM91A1, FAM92A, FAM92B, FAM95C, FAM96A, FAM96B, FAM98A,FAM98B, FAM98C, FAM9A, FAM9B, FAM9C, FAN1, FANCA, FANCB, FANCC, FANCD2,FANCD2OS, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FANK1, FAP, FAR1,FAR2, FARP1, FARP2, FARS2, FARSA, FARSB, FAS, FASLG, FASN, FASTK,FASTKD1, FASTKD2, FASTKD3, FASTKD5, FAT1, FAT2, FAT3, FAT4, FATE1, FAU,FAXC, FAXDC2, FBF1, FBL, FBLIM1, FBLL1, FBLN1, FBLN2, FBLN5, FBLN7,FBN1, FBN2, FBN3, FBP1, FBP2, FBRS, FBRSL1, FBXL12, FBXL13, FBXL14,FBXL15, FBXL16, FBXL17, FBXL18, FBXL19, FBXL2, FBXL20, FBXL22, FBXL3,FBXL4, FBXL5, FBXL6, FBXL7, FBXL8, FBXO10, FBXO11, FBXO15, FBXO16,FBXO17, FBXO18, FBXO2, FBXO21, FBXO22, FBXO24, FBXO25, FBXO27, FBXO28,FBXO3, FBXO30, FBXO31, FBXO32, FBXO33, FBXO34, FBXO36, FBXO38, FBXO39,FBXO4, FBXO40, FBXO41, FBXO42, FBXO43, FBXO44, FBXO45, FBXO46, FBXO47,FBXO48, FBXO5, FBXO6, FBXO7, FBXO8, FBXO9, FBW10, FBXW11, FBXW12, FBXW2,FBXW4, FBXW5, FBXW7, FBXW8, FBXW9, FCAMR, FCAR, FCER1A, FCER1G, FCER2,FCF1, FCGBP, FCGR1A, FCGR1B, FCGR2A, FCGR2B, FCGR2C, FCGR3A, FCGR3B,FCGRT, FCHO1, FCHO2, FCHSD1, FCHSD2, FCMR, FCN1, FCN2, FCN3, FCRL1,FCRL2, FCRL3, FCRL4, FCRL5, FCRL6, FCRLA, FCRLB, FDCSP, FDFT1, FDPS,FDX1, FDX2, FDXACB1, FDXR, FECH, FEM1A, FEM1B, FEM1C, FEN1, FER, FER1L5,FER1L6, FERD3L, FERMT1, FERMT2, FERMT3, FES, FETUB, FEV, FEZ1, FEZ2,FEZF1, FEZF2, FFAR1, FFAR2, FFAR3, FFAR4, FGA, FGB, FGD1, FGD2, FGD3,FGD4, FGD5, FGD6, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF16, FGF17,FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6,FGF7, FGF8, FGF9, FGFBP1, FGFBP2, FGFBP3, FGFR1, FGFR1OP, FGFR1OP2,FGFR2, FGFR3, FGFR4, FGFRL1, FGG, FGGY, FGL1, FGL2, FGR, FH, FHAD1,FHDC1, FHIT, FHL1, FHL2, FHL3, FHL5, FHOD1, FHOD3, FIBCD1, FIBIN, FIBP,FICD, FIG4, FIGLA, FIGN, FIGNL1, FIGNL2, FILIP1, FILIP1L, FIP1L1, FIS1,FITM1, FITM2, FIZ1, FJX1, FKBP10, FKBP11, FKBP14, FKBP15, FKBP1A,FKBP1B, FKBP1C, FKBP2, FKBP3, FKBP4, FKBP5, FKBP6, FKBP7, FKBP8, FKBP9,FKBPL, FKRP, FKTN, FLAD1, FLCN, FLG, FLG2, FLI1, FLIT, FLNA, FLNB, FLNC,FLOT1, FLOT2, FLRT1, FLRT2, FLRT3, FLT1, FLT3, FLT3LG, FLT4, FLVCR1,FLVCR2, FLYWCH1, FLYWCH2, FMC1, FMN1, FMN2, FMNL1, FMNL2, FMNL3, FMO1,FMO2, FMO3, FMO4, FMO5, FMOD, FMR1, FMR1NB, FN1, FN3K, FN3KRP, FNBP1,FNBP1L, FNBP4, FNDC1, FNDC10, FNDC11, FNDC3A, FNDC3B, FNDC4, FNDC5,FNDC7, FNDC8, FNDC9, FNIP1, FNIP2, FNTA, FNTB, F0681492.1, F0681542.1,FOCAD, FOLH1, FOLR1, FOLR2, FOLR3, FOPNL, FOS, FOSB, FOSL1, FOSL2,FOXA1, FOXA2, FOXA3, FOXB1, FOXB2, FOXC1, FOXC2, FOXD1, FOXD2, FOXD3,FOXD4, FOXD4L1, FOXD4L3, FOXD4L4, FOXD4L5, FOXD4L6, FOXE1, FOXE3, FOXF1,FOXF2, FOXG1, FOXH1, FOXI1, FOXI2, FOXI3, FOXJ1, FOXJ2, FOXJ3, FOXK1,FOXK2, FOXL1, FOXL2, FOXL2NB, FOXM1, FOXN1, FOXN2, FOXN3, FOXN4, FOXO1,FOXO3, FOXO4, FOXO6, FOXP1, FOXP2, FOXP3, FOXP4, FOXQ1, FOXR1, FOXR2,FOXRED1, FOXRED2, FOXS1, FP236240.1, FP565260.1, FP565260.2, FP565260.3,FP565260.4, FP565260.6, FP565260.7, FP565324.1, FP565324.2, FPGS, FPGT,FPGT-TNNI3K, FPR1, FPR2, FPR3, FRA10AC1, FRAS1, FRAT1, FRAT2, FREM1,FREM2, FREM3, FRG1, FRG2, FRG2B, FRG2C, FRK, FRMD1, FRMD3, FRMD4A,FRMD4B, FRMD5, FRMD6, FRMD7, FRMD8, FRMPD1, FRMPD2, FRMPD3, FRMPD4,FRRS1, FRRS1L, FRS2, FRS3, FRY, FRYL, FRZB, FSBP, FSCB, FSCN1, FSCN2,FSCN3, FSD1, FSD1L, FSD2, FSHB, FSHR, FSIP1, FSIP2, FST, FSTL1, FSTL3,FSTL4, FSTL5, FTCD, FTCDNL1, FTH1, FTHL17, FTL, FTMT, FTO, FTSJ1, FTSJ3,FUBP1, FUBP3, FUCA1, FUCA2, FUK, FUNDC1, FUNDC2, FUOM, FURIN, FUS, FUT1,FUT10, FUT11, FUT2, FUT3, FUT4, FUT5, FUT6, FUT7, FUT8, FUT9, FUZ, FXN,FXR1, FXR2, FXYD1, FXYD2, FXYD3, FXYD4, FXYD5, FXYD6, FXYD6-FXYD2,FXYD7, FYB1, FYB2, FYCO1, FYN, FYTTD1, FZD1, FZD10, FZD2, FZD3, FZD4,FZD5, FZD6, FZD7, FZD8, FZD9, FZR1, GOS2, G2E3, G3BP1, G3BP2, G6PC,G6PC2, G6PC3, G6PD, GAA, GAB1, GAB2, GAB3, GAB4, GABARAP, GABARAPL1,GABARAPL2, GABBR1, GABBR2, GABPA, GABPB1, GABPB2, GABRA1, GABRA2,GABRA3, GABRA4, GABRA5, GABRA6, GABRB1, GABRB2, GABRB3, GABRD, GABRE,GABRG1, GABRG2, GABRG3, GABRP, GABRQ, GABRR1, GABRR2, GABRR3, GAD1,GAD2, GADD45A, GADD45B, GADD45G, GADD45GIP1, GADL1, GAGE1, GAGE10,GAGE12B, GAGE12C, GAGE12D, GAGE12E, GAGE12F, GAGE12G, GAGE12H, GAGE12J,GAGE13, GAGE2A, GAGE2E, GAK, GAL, GAL3ST1, GAL3ST2, GAL3ST3, GAL3ST4,GALC, GALE, GALK1, GALK2, GALM, GALNS, GALNT 1, GALNT 10, GALNT 11,GALNT12, GALNT13, GALNT 14, GALNT15, GALNT16, GALNT17, GALNT18, GALNT2,GALNT3, GALNT4, GALNT5, GALNT6, GALNT7, GALNT8, GALNT9, GALNTL5,GALNTL6, GALP, GALR1, GALR2, GALR3, GALT, GAMT, GAN, GANAB, GANC, GAP43,GAPDH, GAPDHS, GAPT, GAPVD1, GAR1, GAREM1, GAREM2, GARNL3, GARS, GART,GAS1, GAS2, GAS2L1, GAS2L2, GAS2L3, GAS6, GAS7, GAS8, GAST, GATA1,GATA2, GATA3, GATA4, GATA5, GATA6, GATAD1, GATAD2A, GATAD2B, GATB, GATC,GATD1, GATM, GATS, GBA, GBA2, GBA3, GBE1, GBF1, GBGT1, GBP1, GBP2, GBP3,GBP4, GBP5, GBP6, GBP7, GBX1, GBX2, GC, GCA, GCAT, GCC1, GCC2, GCDH,GCFC2, GCG, GCGR, GCH1, GCHFR, GCK, GCKR, GCLC, GCLM, GCM1, GCM2, GCN1,GCNA, GCNT1, GCNT2, GCNT3, GCNT4, GCNT7, GCOM1, GCSAM, GCSAML, GCSH,GDA, GDAP1, GDAP1L1, GDAP2, GDE1, GDF1, GDF10, GDF11, GDF15, GDF2, GDF3,GDF5, GDF50S, GDF6, GDF7, GDF9, GDI1, GDI2, GDNF, GDPD1, GDPD2, GDPD3,GDPD4, GDPD5, GDPGP1, GEM, GEMIN2, GEMIN4, GEMIN5, GEMIN6, GEMINI,GEMIN8, GEN1, GET4, GFAP, GFER, GFI1, GFI1B, GFM1, GFM2, GFOD1, GFOD2,GFPT1, GFPT2, GFRA1, GFRA2, GFRA3, GFRA4, GFRAL, GFY, GGA1, GGA2, GGA3,GGACT, GGCT, GGCX, GGH, GGN, GGNBP2, GGPS1, GGT1, GGT2, GGT5, GGT6,GGT7, GGTLC1, GGTLC2, GGTLC3, GH1, GH2, GHDC, GHITM, GHR, GHRH, GHRHR,GHRL, GHSR, GID4, GID8, GIF, GIGYF1, GIGYF2, GIMAP1, GIMAP1-GIMAP5,GIMAP2, GIMAP4, GIMAP5, GIMAP6, GIMAP7, GIMAP8, GIMD1, GIN1, GINM1,GINS1, GINS2, GINS3, GINS4, GIP, GIPC1, GIPC2, GIPC3, GIPR, GIT1, GIT2,GJA1, GJA10, GJA3, GJA4, GJA5, GJA8, GJA9, GJB1, GJB2, GJB3, GJB4, GJB5,GJB6, GJB7, GJC1, GJC2, GJC3, GJD2, GJD3, GJD4, GJE1, GK, GK2, GK3P,GK5, GKAP1, GKN1, GKN2, GLA, GLB1, GLB1L, GLB1L2, GLB1L3, GLCCI1, GLCE,GLDC, GLDN, GLE1, GLG1, GLI1, GLI2, GLI3, GLI4, GLIPR1, GLIPR1L1,GLIPR1L2, GLIPR2, GLIS1, GLIS2, GLIS3, GLMN, GLMP, GLO1, GLOD4, GLOD5,GLP1R, GLP2R, GLRA1, GLRA2, GLRA3, GLRA4, GLRB, GLRX, GLRX2, GLRX3,GLRX5, GLS, GLS2, GLT1D1, GLT6D1, GLT8D1, GLT8D2, GLTP, GLTPD2, GLUD1,GLUD2, GLUL, GLYAT, GLYATL1, GLYATL1P3, GLYATL2, GLYATL3, GLYCTK, GLYR1,GM2A, GMCL1, GMDS, GMEB1, GMEB2, GMFB, GMFG, GMIP, GML, GMNC, GMNN,GMPPA, GMPPB, GMPR, GMPR2, GMPS, GNA11, GNA12, GNA13, GNA14, GNA15,GNAI1, GNAI2, GNAI3, GNAL, GNAO1, GNAQ, GNAS, GNAT1, GNAT2, GNAT3, GNAZ,GNB1, GNB1L, GNB2, GNB3, GNB4, GNB5, GNE, GNG10, GNG11, GNG12, GNG13,GNG14, GNG2, GNG3, GNG4, GNG5, GNG7, GNG8, GNGT1, GNGT2, GNL1, GNL2,GNL3, GNL3L, GNLY, GNMT, GNPAT, GNPDA1, GNPDA2, GNPNAT1, GNPTAB, GNPTG,GNRH1, GNRH2, GNRHR, GNS, GOLGA1, GOLGA2, GOLGA3, GOLGA4, GOLGA5,GOLGA6A, GOLGA6B, GOLGA6C, GOLGA6D, GOLGA6L1, GOLGA6L10, GOLGA6L2,GOLGA6L22, GOLGA6L4, GOLGA6L6, GOLGA6L7P, GOLGA6L9, GOLGA7, GOLGA7B,GOLGA8A, GOLGA8B, GOLGA8F, GOLGA8G, GOLGA8H, GOLGA8J, GOLGA8K, GOLGA8M,GOLGA8N, GOLGA8O, GOLGA8Q, GOLGA8R, GOLGA8S, GOLGA8T, GOLGB1, GOLIM4,GOLM1, GOLPH3, GOLPH3L, GOLT1A, GOLT1B, GON4L, GON7, GOPC, GORAB,GORASP1, GORASP2, GOSR1, GOSR2, GOT1, GOT1L1, GOT2, GP1BA, GP1BB, GP2,GP5, GP6, GP9, GPA33, GPAA1, GPALPP1, GPAM, GPANK1, GPAT2, GPAT3, GPAT4,GPATCH1, GPATCH11, GPATCH2, GPATCH2L, GPATCH3, GPATCH4, GPATCH8, GPBAR1,GPBP1, GPBP1L1, GPC1, GPC2, GPC3, GPC4, GPC5, GPC6, GPCPD1, GPD1, GPD1L,GPD2, GPER1, GPHA2, GPHB5, GPHN, GPI, GPIHBP1, GPKOW, GPLD1, GPM6A,GPM6B, GPN1, GPN2, GPN3, GPNMB, GPR1, GPR101, GPR107, GPR108, GPR119,GPR12, GPR132, GPR135, GPR137, GPR137B, GPR137C, GPR139, GPR141, GPR142,GPR143, GPR146, GPR148, GPR149, GPR15, GPR150, GPR151, GPR152, GPR153,GPR155, GPR156, GPR157, GPR158, GPR160, GPR161, GPR162, GPR17, GPR171,GPR173, GPR174, GPR176, GPR179, GPR18, GPR180, GPR182, GPR183, GPR19,GPR20, GPR21, GPR22, GPR25, GPR26, GPR27, GPR3, GPR31, GPR32, GPR33,GPR34, GPR35, GPR37, GPR37L1, GPR39, GPR4, GPR42, GPR45, GPR50, GPR52,GPR55, GPR6, GPR61, GPR62, GPR63, GPR65, GPR68, GPR75, GPR75-ASB3,GPR78, GPR82, GPR83, GPR84, GPR85, GPR87, GPR88, GPR89A, GPR89B,GPRASP1, GPRASP2, GPRC5A, GPRC5B, GPRC5C, GPRC5D, GPRC6A, GPRIN1,GPRIN2, GPRIN3, GPS1, GPS2, GPSM1, GPSM2, GPSM3, GPT, GPT2, GPX1, GPX2,GPX3, GPX4, GPX5, GPX6, GPX7, GPX8, GRAMD1A, GRAMD1B, GRAMD1C, GRAMD2A,GRAMD2B, GRAMD4, GRAP, GRAP2, GRAPL, GRASP, GRB10, GRB14, GRB2, GRB7,GREB1, GREB1L, GREM1, GREM2, GRHL1, GRHL2, GRHL3, GRHPR, GRIA1, GRIA2,GRIA3, GRIA4, GRID1, GRID2, GRID2IP, GRIFIN, GRIK1, GRIK2, GRIK3, GRIK4,GRIK5, GRIN1, GRIN2A, GRIN2B, GRIN2C, GRIN2D, GRIN3A, GRIN3B, GRINA,GRIP1, GRIP2, GRIPAP1, GRK1, GRK2, GRK3, GRK4, GRK5, GRK6, GRK7, GRM1,GRM2, GRM3, GRM4, GRM5, GRM6, GRM7, GRM8, GRN, GRP, GRPEL1, GRPEL2,GRPR, GRSF1, GRTP1, GRWD1, GRXCR1, GRXCR2, GSAP, GSC, GSC2, GSDMA,GSDMB, GSDMC, GSDMD, GSE1, GSG1, GSG1L, GSG1L2, GSK3A, GSK3B, GSKIP,GSN, GSPT1, GSPT2, GSR, GSS, GSTA1, GSTA2, GSTA3, GSTA4, GSTA5, GSTCD,GSTK1, GSTM1, GSTM2, GSTM3, GSTM4, GSTM5, GSTO1, GSTO2, GSTP1, GSTT1,GSTT2, GSTT2B, GSTTP1, GSTZ1, GSX1, GSX2, GTDC1, GTF2A1, GTF2A1L,GTF2A2, GTF2B, GTF2E1, GTF2E2, GTF2F1, GTF2F2, GTF2H1, GTF2H2, GTF2H2C,GTF2H2C2, GTF2H3, GTF2H4, GTF2H5, GTF2I, GTF2IRD1, GTF2IRD2, GTF2IRD2B,GTF3A, GTF3C1, GTF3C2, GTF3C3, GTF3C4, GTF3C5, GTF3C6, GTPBP1, GTPBP10,GTPBP2, GTPBP3, GTPBP4, GTPBP6, GTPBP8, GTSE1, GTSF1, GTSF1L,GU182339.1, GU182339.3, GU182343.1, GU182343.2, GU182345.1, GU182345.2,GU182347.1, GU182351.2, GU182352.2, GU182353.1, GU182355.1, GU182355.2,GU182355.3, GU182357.1, GU182357.3, GU182359.1, GU182359.2, GUCA1A,GUCA1B, GUCA1C, GUCA2A, GUCA2B, GUCD1, GUCY1A2, GUCY1A3, GUCY1B3,GUCY2C, GUCY2D, GUCY2F, GUF1, GUK1, GULP1, GUSB, GVQW2, GXYLT1, GXYLT2,GYG1, GYG2, GYPA, GYPB, GYPC, GYPE, GYS1, GPS2, GZF1, GZMA, GZMB, GZMH,GZMK, GZMM, H1F0, H1FNT, H1FOO, H1FX, H2AFB1, H2AFB2, H2AFB3, H2AFJ,H2AFV, H2AFX, H2AFY, H2AFY2, H2AFZ, H2BFM, H2BFS, H2BFWT, H3F3A, H3F3B,H3F3C, H6PD, HAAO, HABP2, HABP4, HACD1, HACD2, HACD3, HACD4, HACE1,HACL1, HADH, HADHA, HADHB, HAGH, HAGHL, HAL, HAMP, HAND1, HAND2, HAO1,HAO2, HAP1, HAPLN1, HAPLN2, HAPLN3, HAPLN4, HARBI1, HARS, HARS2, HAS1,HAS2, HAS3, HASPIN, HAT1, HAUS1, HAUS2, HAUS3, HAUS4, HAUS5, HAUS6,HAUS7, HAUS8, HAVCR1, HAVCR2, HAX1, HBA1, HBA2, HBB, HBD, HBE1, HBEGF,HBG1, HBG2, HBM, HBP1, HBQ1, HBS1L, HBZ, HCAR1, HCAR2, HCAR3, HCCS,HCFC1, HCFC1R1, HCFC2, HCK, HCLS1, HCN1, HCN2, HCN3, HCN4, HCRT, HCRTR1,HCRTR2, HCST, HDAC1, HDAC10, HDAC11, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6,HDAC7, HDAC8, HDAC9, HDC, HDDC2, HDDC3, HDGF, HDGFL1, HDGFL2, HDGFL3,HDHD2, HDHD3, HDHD5, HDLBP, HDX, HEATR1, HEATR3, HEATR4, HEATR5A,HEATR5B, HEATR6, HEATR9, HEBP1, HEBP2, HECA, HECTD1, HECTD2, HECTD3,HECTD4, HECW1, HECW2, HEG1, HELB, HELLS, HELQ, HELT, HELZ, HELZ2, HEMGN,HEMK1, HENMT1, HEPACAM, HEPACAM2, HEPH, HEPHL1, HEPN1, HERC1, HERC2,HERC3, HERC4, HERC5, HERC6, HERPUD1, HERPUD2, HES1, HES2, HES3, HES4,HESS, HES6, HES7, HESX1, HEXA, HEXB, HEXDC, HEXIM1, HEXIM2, HEY1, HEY2,HEYL, HFE, HFE2, HFM1, HGD, HGF, HGFAC, HGH1, HGNC:18790, HGNC:24955,HGS, HGSNAT, HHAT, HHATL, HHEX, HHIP, HHIPL1, HHIPL2, HHLA1, HHLA2,HHLA3, HIBADH, HIBCH, HIC1, HIC2, HID1, HIF1A, HIF1AN, HIF3A, HIGD1A,HIGD1B, HIGD1C, HIGD2A, HIGD2B, HIKESHI, HILPDA, HINFP, HINT1, HINT2,HINT3, HIP1, HIP1R, HIPK1, HIPK2, HIPK3, HIPK4, HIRA, HIRIP3, HIST1H1A,HIST1H1B, HIST1H1C, HIST1H1D, HIST1H1E, HIST1H1T, HIST1H2AA, HIST1H2AB,HIST1H2AC, HIST1H2AD, HIST1H2AE, HIST1H2AG, HIST1H2AH, HIST1H2AI,HIST1H2AJ, HIST1H2AK, HIST1H2AL, HIST1H2AM, HIST1H2BA, HIST1H2BB,HIST1H2BC, HIST1H2BD, HIST1H2BE, HIST1H2BF, HIST1H2BG, HIST1H2BH,HIST1H2BI, HIST1H2BJ, HIST1H2BK, HIST1H2BL, HIST1H2BM, HIST1H2BN,HIST1H2BO, HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F,HIST1H3G, HIST1H3H, HIST1H3I, HIST1H3J, HIST1H4A, HIST1H4B, HIST1H4C,HIST1H4D, HIST1H4E, HIST1H4F, HIST1H4G, HIST1H4H, HIST1H4I, HIST1H4J,HIST1H4K, HIST1H4L, HIST2H2AA3, HIST2H2AA4, HIST2H2AB, HIST2H2AC,HIST2H2BE, HIST2H2BF, HIST2H3A, HIST2H3C, HIST2H3D, HIST2H3PS2,HIST2H4A, HIST2H4B, HIST3H2A, HIST3H2BB, HIST3H3, HIST4H4, HIVEP1,HIVEP2, HIVEP3, HJURP, HK1, HK2, HK3, HKDC1, HKR1, HLA-A, HLA-B, HLA-C,HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA1,HLA-DQA2, HLA-DQB1, HLA-DQB2, HLA-DRA, HLA-DRB1, HLA-DRB3, HLA-DRB4,HLA-DRB5, HLA-E, HLA-F, HLA-G, HLCS, HLF, HLTF, HLX, HM13, HM190170.1,HMBOX1, HMBS, HMCES, HMCN1, HMCN2, HMG20A, HMG20B, HMGA1, HMGA2, HMGB1,HMGB2, HMGB3, HMGB4, HMGCL, HMGCLL1, HMGCR, HMGCS1, HMGCS2, HMGN1,HMGN2, HMGN3, HMGN4, HMGN5, HMGXB3, HMGXB4, HMHB1, HMMR, HMOX1, HMOX2,HMSD, HMX1, HMX2, HMX3, HNF1A, HNF1B, HNF4A, HNF4G, HNMT, HNRNPA0,HNRNPA1, HNRNPA1L2, HNRNPA2B1, HNRNPA3, HNRNPAB, HNRNPC, HNRNPCL1,HNRNPCL2, HNRNPCL3, HNRNPCL4, HNRNPD, HNRNPDL, HNRNPF, HNRNPH1, HNRNPH2,HNRNPH3, HNRNPK, HNRNPL, HNRNPLL, HNRNPM, HNRNPR, HNRNPU, HNRNPUL1,HNRNPUL2, HNRNPUL2-BSCL2, HOGA1, HOMER1, HOMER2, HOMER3, HOMEZ, HOOK1,HOOK2, HOOK3, HOPX, HORMAD1, HORMAD2, HOXA1, HOXA10, HOXA11, HOXA13,HOXA2, HOXA3, HOXA4, HOXA5, HOXA6, HOXA7, HOXA9, HOXB1, HOXB13, HOXB2,HOXB3, HOXB4, HOXB5, HOXB6, HOXB7, HOXB8, HOXB9, HOXC10, HOXC11, HOXC12,HOXC13, HOXC4, HOXC5, HOXC6, HOXC8, HOXC9, HOXD1, HOXD10, HOXD11,HOXD12, HOXD13, HOXD3, HOXD4, HOXD8, HOXD9, HP, HP1BP3, HPCA, HPCAL1,HPCAL4, HPD, HPDL, HPF1, HPGD, HPGDS, HPN, HPR, HPRT1, HPS1, HPS3, HPS4,HPS5, HPS6, HPSE, HPSE2, HPX, HR, HRAS, HRASLS, HRASLS2, HRASLS5, HRC,HRCT1, HRG, HRH1, HRH2, HRH3, HRH4, HRK, HRNR, HS1BP3, HS2ST1, HS3ST1,HS3ST2, HS3ST3A1, HS3ST3B1, HS3ST4, HS3ST5, HS3ST6, HS6ST1, HS6ST2,HS6ST3, HSBP1, HSBP1L1, HSCB, HSD11B1, HSD11B1L, HSD11B2, HSD17B1,HSD17B10, HSD17B11, HSD17B12, HSD17B13, HSD17B14, HSD17B2, HSD17B3,HSD17B4, HSD17B6, HSD17B7, HSD17B8, HSD3B1, HSD3B2, HSD3B7, HSDL1,HSDL2, HSF1, HSF2, HSF2BP, HSF4, HSF5, HSFX1, HSFX2, HSFX3, HSFX4,HSFY1, HSFY2, HSH2D, HSP90AA1, HSP90AB1, HSP90B1, HSPA12A, HSPA12B,HSPA13, HSPA14, HSPA1A, HSPA1B, HSPA1L, HSPA2, HSPA4, HSPA4L, HSPA5,HSPA6, HSPA8, HSPA9, HSPB1, HSPB11, HSPB2, HSPB2-C11orf52, HSPB3, HSPB6,HSPB7, HSPB8, HSPB9, HSPBAP1, HSPBP1, HSPD1, HSPE1, HSPE1-MOB4, HSPG2,HSPH1, HTATIP2, HTATSF1, HTD2, HTN1, HTN3, HTR1A, HTR1B, HTR1D, HTR1E,HTR1F, HTR2A, HTR2B, HTR2C, HTR3A, HTR3B, HTR3C, HTR3D, HTR3E, HTR4,HTR5A, HTR6, HTR7, HTRA1, HTRA2, HTRA3, HTRA4, HTT, HUNK, HUS1, HUS1B,HUWE1, HVCN1, HYAL1, HYAL2, HYAL3, HYAL4, HYDIN, HYI, HYKK, HYLS1,HYOU1, HYPK, HYPM, IAH1, IAPP, IARS, IARS2, IBA57, IBSP, IBTK, ICA1,ICA1L, ICAM1, ICAM2, ICAM3, ICAM4, ICAM5, ICE1, ICE2, ICK, ICMT, ICOS,ICOSLG, ID1, ID2, ID3, ID4, IDE, IDH1, IDH2, IDH3A, IDH3B, IDH3G, IDI1,IDI2, IDNK, IDO1, IDO2, IDS, IDUA, IER2, IER3, IER3IP1, IER5, IER5L,IFFO1, IFFO2, IFI16, IFI27, IFI27L1, IFI27L2, IFI30, IFI35, IFI44,IFI44L, IFI6, IFIH1, IFIT1, IFIT1B, IFIT2, IFIT3, IFIT5, IFITM1,IFITM10, IFITM2, IFITM3, IFITM5, IFNA1, IFNA10, IFNA13, IFNA14, IFNA16,IFNA17, IFNA2, IFNA21, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNAR1,IFNAR2, IFNB1, IFNE, IFNG, IFNGR1, IFNGR2, IFNK, IFNL1, IFNL2, IFNL3,IFNL4, IFNLR1, IFNW1, IFRD1, IFRD2, IFT122, IFT140, IFT172, IFT20,IFT22, IFT27, IFT43, IFT46, IFT52, IFT57, IFT74, IFT80, IFT81, IFT88,IGBP1, IGDCC3, IGDCC4, IGF1, IGF1R, IGF2, IGF2BP1, IGF2BP2, IGF2BP3,IGF2R, IGFALS, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IGFBP7,IGFBPL1, IGFL1, IGFL2, IGFL3, IGFL4, IGFLR1, IGFN1, IGHA1, IGHA2, IGHD,IGHD1-1, IGHD1-14, IGHD1-20, IGHD1-26, IGHD1-7, IGHD1OR15-1A,IGHD1OR15-1B, IGHD2-15, IGHD2-2, IGHD2-21, IGHD2-8, IGHD2OR15-2A,IGHD2OR15-2B, IGHD3-10, IGHD3-16, IGHD3-22, IGHD3-3, IGHD3-9,IGHD3OR15-3A, IGHD3OR15-3B, IGHD4-11, IGHD4-17, IGHD4-23, IGHD4-4,IGHD4OR15-4A, IGHD4OR15-4B, IGHD5-12, IGHD5-18, IGHD5-24, IGHD5-5,IGHD5OR15-5A, IGHD5OR15-5B, IGHD6-13, IGHD6-19, IGHD6-25, IGHD6-6,IGHD7-27, IGHE, IGHG1, IGHG2, IGHG3, IGHG4, IGHJ1, IGHJ2, IGHJ3, IGHJ4,IGHJ5, IGHJ6, IGHM, IGHMBP2, IGHV1-18, IGHV1-2, IGHV1-24, IGHV1-3,IGHV1-45, IGHV1-46, IGHV1-58, IGHV1-69, IGHV1OR15-1, IGHV1OR15-9,IGHV1OR21-1, IGHV2-26, IGHV2-5, IGHV2-70, IGHV2OR16-5, IGHV3-11,IGHV3-13, IGHV3-15, IGHV3-16, IGHV3-20, IGHV3-21, IGHV3-23, IGHV3-30,IGHV3-33, IGHV3-35, IGHV3-38, IGHV3-43, IGHV3-48, IGHV3-49, IGHV3-53,IGHV3-64, IGHV3-66, IGHV3-7, IGHV3-72, IGHV3-73, IGHV3-74, IGHV3OR1-7,IGHV3OR16-10, IGHV3OR16-12, IGHV3OR16-13, IGHV3OR16-8, IGHV3OR16-9,IGHV4-28, IGHV4-31, IGHV4-34, IGHV4-39, IGHV4-4, IGHV4-59, IGHV4-61,IGHV4OR15-8, IGHV5-51, IGHV6-1, IGHV7-81, IGIP, IGKC, IGKJ1, IGKJ2,IGKJ3, IGKJ4, IGKJ5, IGKV1-12, IGKV1-16, IGKV1-17, IGKV1-27, IGKV1-33,IGKV1-37, IGKV1-39, IGKV1-5, IGKV1-6, IGKV1-8, IGKV1-9, IGKV1D-12,IGKV1D-13, IGKV1D-16, IGKV1D-17, IGKV1D-33, IGKV1D-37, IGKV1D-39,IGKV1D-42, IGKV1D-43, IGKV1D-8, IGKV10R2-108, IGKV2-24, IGKV2-28,IGKV2-30, IGKV2-40, IGKV2D-24, IGKV2D-26, IGKV2D-28, IGKV2D-29,IGKV2D-30, IGKV2D-40, IGKV3-11, IGKV3-15, IGKV3-20, IGKV3-7, IGKV3D-11,IGKV3D-15, IGKV3D-20, IGKV3D-7, IGKV3OR2-268, IGKV4-1, IGKV5-2,IGKV6-21, IGKV6D-21, IGKV6D-41, IGLC1, IGLC2, IGLC3, IGLC7, IGLJ1,IGLJ2, IGLJ3, IGLJ4, IGLJ5, IGLJ6, IGLJ7, IGLL1, IGLL5, IGLON5,IGLV10-54, IGLV11-55, IGLV1-36, IGLV1-40, IGLV1-44, IGLV1-47, IGLV1-50,IGLV1-51, IGLV2-11, IGLV2-14, IGLV2-18, IGLV2-23, IGLV2-33, IGLV2-8,IGLV3-1, IGLV3-10, IGLV3-12, IGLV3-16, IGLV3-19, IGLV3-21, IGLV3-22,IGLV3-25, IGLV3-27, IGLV3-32, IGLV3-9, IGLV4-3, IGLV4-60, IGLV4-69,IGLV5-37, IGLV5-45, IGLV5-48, IGLV5-52, IGLV6-57, IGLV7-43, IGLV7-46,IGLV8-61, IGLV9-49, IGSF1, IGSF10, IGSF11, IGSF21, IGSF22, IGSF23,IGSF3, IGSF5, IGSF6, IGSF8, IGSF9, IGSF9B, IHH, IK, IKBIP, IKBKB, IKBKE,IKBKG, IKZF1, IKZF2, IKZF3, IKZF4, IKZF5, IL10, IL10RA, IL10RB, IL11,IL11RA, IL12A, IL12B, IL12RB1, IL12RB2, IL13, IL13RA1, IL13RA2, IL15,IL15RA, IL16, IL17A, IL17B, IL17C, IL17D, IL17F, IL17RA, IL17RB, IL17RC,IL17RD, IL17RE, IL17REL, IL18, IL18BP, IL18R1, IL18RAP, IL19, IL1A,IL1B, IL1F10, IL1R1, IL1R2, IL1RAP, IL1RAPL1, IL1RAPL2, IL1RL1, IL1RL2,IL1RN, IL2, IL20, IL20RA, IL20RB, IL21, IL21R, IL22, IL22RA1, IL22RA2,IL23A, IL23R, IL24, IL25, IL26, IL27, IL27RA, IL2RA, IL2RB, IL2RG, IL3,IL31, IL31RA, IL32, IL33, IL34, IL36A, IL36B, IL36G, IL36RN, IL37,IL3RA, IL4, IL4I1, IL4R, IL5, IL5RA, IL6, IL6R, IL6ST, IL7, IL7R, IL9,IL9R, ILDR1, ILDR2, ILF2, ILF3, ILK, ILKAP, ILVBL, IMMP1L, IMMP2L, IMMT,IMP3, IMP4, IMPA1, IMPA2, IMPACT, IMPAD1, IMPDH1, IMPDH2, IMPG1, IMPG2,INA, INAFM1, INAFM2, INAVA, INCA1, INCENP, INF2, ING1, ING2, ING3, ING4,ING5, INHA, INHBA, INHBB, INHBC, INHBE, INIP, INMT, INMT-MINDY4, INO80,INO80B, INO80B-WBP1, INO80C, INO80D, INO80E, INPP1, INPP4A, INPP4B,INPP5A, INPP5B, INPP5D, INPP5E, INPP5F, INPP5J, INPP5K, INPPL1, INS,INSC, INSIG1, INSIG2, INS-IGF2, INSL3, INSL4, INSL5, INSL6, INSM1,INSM2, INSR, INSRR, INTS1, INTS10, INTS11, INTS12, INTS13, INTS14,INTS2, INTS3, INTS4, INTS5, INTS6, INTS6L, INTS7, INTS8, INTS9, INTU,INVS, IP6K1, IP6K2, IP6K3, IPCEF1, IPMK, IPO11, IPO13, IPO4, IPO5, IPO7,IPO8, IPO9, IPP, IPPK, IQANK1, IQCA1, IQCA1L, IQCB1, IQCC, IQCD, IQCE,IQCF1, IQCF2, IQCF3, IQCF5, IQCF6, IQCG, IQCH, IQCJ, IQCJ-SCHIP1, IQCK,IQCM, IQGAP1, IQGAP2, IQGAP3, IQSEC1, IQSEC2, IQSEC3, IQUB, IREB2, IRF1,IRF2, IRF2BP1, IRF2BP2, IRF2BPL, IRF3, IRF4, IRF5, IRF6, IRF7, IRF8,IRF9, IRGC, IRGM, IRGQ, IRS1, IRS2, IRS4, IRX1, IRX2, IRX3, IRX4, IRX5,IRX6, ISCA1, ISCA2, ISCU, ISG15, ISG20, ISG20L2, ISL1, ISL2, ISLR,ISLR2, ISM1, ISM2, ISOC1, ISOC2, ISPD, IST1, ISX, ISY1, ISY1-RAB43,ISYNA1, ITCH, ITFG1, ITFG2, ITGA1, ITGA10, ITGA11, ITGA2, ITGA2B, ITGA3,ITGA4, ITGA5, ITGA6, ITGA7, ITGA8, ITGA9, ITGAD, ITGAE, ITGAL, ITGAM,ITGAV, ITGAX, ITGB1, ITGB1BP1, ITGB1BP2, ITGB2, ITGB3, ITGB3BP, ITGB4,ITGB5, ITGB6, ITGB7, ITGB8, ITGBL1, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5,ITIH6, ITK, ITLN1, ITLN2, ITM2A, ITM2B, ITM2C, ITPA, ITPK1, ITPKA,ITPKB, ITPKC, ITPR1, ITPR2, ITPR3, ITPRIP, ITPRIPL1, ITPRIPL2, ITSN1,ITSN2, IVD, IVL, IVNS1ABP, IWS1, IYD, IZUMO1, IZUMO1R, IZUMO2, IZUMO3,IZUMO4, JADE1, JADE2, JADE3, JAG1, JAG2, JAGN1, JAK1, JAK2, JAK3,JAKMIP1, JAKMIP2, JAKMIP3, JAM2, JAM3, JAML, JARID2, JAZF1, JCAD,JCHAIN, JDP2, JKAMP, JMJD1C, JMJD4, JMJD6, JMJD7, JMJD7-PLA2G4B, JMJD8,JMY, JOSD1, JOSD2, JPH1, JPH2, JPH3, JPH4, JPT1, JPT2, JRK, JRKL, JSRP1,JTB, JUN, JUNB, JUND, JUP, KAAG1, KALRN, KANK1, KANK2, KANK3, KANK4,KANSL1, KANSL1L, KANSL2, KANSL3, KANTR, KARS, KAT14, KAT2A, KAT2B, KAT5,KAT6A, KAT6B, KAT7, KAT8, KATNA1, KATNAL1, KATNAL2, KATNB1, KATNBL1,KAZALD1, KAZN, KBTBD11, KBTBD11-OT1, KBTBD12, KBTBD13, KBTBD2, KBTBD3,KBTBD4, KBTBD6, KBTBD7, KBTBD8, KCMF1, KCNA1, KCNA10, KCNA2, KCNA3,KCNA4, KCNA5, KCNA7, KCNAB1, KCNAB2, KCNAB3, KCNB1, KCNB2, KCNC1, KCNC2,KCNC3, KCNC4, KCND1, KCND2, KCND3, KCNE1, KCNE1B, KCNE2, KCNE3, KCNE4,KCNE5, KCNF1, KCNG1, KCNG2, KCNG3, KCNG4, KCNH1, KCNH2, KCNH3, KCNH4,KCNH5, KCNH6, KCNH7, KCNH8, KCNIP1, KCNIP2, KCNIP3, KCNIP4, KCNJ1,KCNJ10, KCNJ11, KCNJ12, KCNJ13, KCNJ14, KCNJ15, KCNJ16, KCNJ18, KCNJ2,KCNJ3, KCNJ4, KCNJ5, KCNJ6, KCNJ8, KCNJ9, KCNK1, KCNK10, KCNK12, KCNK13,KCNK15, KCNK16, KCNK17, KCNK18, KCNK2, KCNK3, KCNK4, KCNK5, KCNK6,KCNK7, KCNK9, KCNMA1, KCNMB1, KCNMB2, KCNMB3, KCNMB4, KCNN1, KCNN2,KCNN3, KCNN4, KCNQ1, KCNQ2, KCNQ3, KCNQ4, KCNQ5, KCNRG, KCNS1, KCNS2,KCNS3, KCNT1, KCNT2, KCNU1, KCNV1, KCNV2, KCP, KCTD1, KCTD10, KCTD11,KCTD12, KCTD13, KCTD14, KCTD15, KCTD16, KCTD17, KCTD18, KCTD19, KCTD2,KCTD20, KCTD21, KCTD3, KCTD4, KCTD5, KCTD6, KCTD7, KCTD8, KCTD9, KDELC1,KDELC2, KDELR1, KDELR2, KDELR3, KDF1, KDM1A, KDM1B, KDM2A, KDM2B, KDM3A,KDM3B, KDM4A, KDM4B, KDM4C, KDM4D, KDM4E, KDM4F, KDM5A, KDM5B, KDM5C,KDM5D, KDM6A, KDM6B, KDM7A, KDM8, KDR, KDSR, KEAP1, KEL, KERA,KF459570.1, KHDC1, KHDC1L, KHDC3L, KHDRBS1, KHDRBS2, KHDRBS3, KHK,KHNYN, KHSRP, KIAA0040, KIAA0100, KIAA0141, KIAA0232, KIAA0319,KIAA0319L, KIAA0355, KIAA0368, KIAA0391, KIAA0408, KIAA0513, KIAA0556,KIAA0586, KIAA0753, KIAA0825, KIAA0895, KIAA0895L, KIAA0907, KIAA0930,KIAA1024, KIAA1024L, KIAA1107, KIAA1109, KIAA1143, KIAA1147, KIAA1161,KIAA1191, KIAA1210, KIAA1211, KIAA1211L, KIAA1217, KIAA1257, KIAA1324,KIAA1324L, KIAA1328, KIAA1456, KIAA1468, KIAA1522, KIAA1524, KIAA1549,KIAA1549L, KIAA1551, KIAA1586, KIAA1614, KIAA1644, KIAA1671, KIAA1683,KIAA1755, KIAA1841, KIAA1958, KIAA2012, KIAA2013, KIAA2026, KIDINS220,KIF11, KIF12, KIF13A, KIF13B, KIF14, KIF15, KIF16B, KIF17, KIF18A,KIF18B, KIF19, KIF1A, KIF1B, KIF1BP, KIF1C, KIF20A, KIF20B, KIF21A,KIF21B, KIF22, KIF23, KIF24, KIF25, KIF26A, KIF26B, KIF27, KIF2A, KIF2B,KIF2C, KIF3A, KIF3B, KIF3C, KIF4A, KIF4B, KIF5A, KIF5B, KIF5C, KIF6,KIF7, KIF9, KIFAP3, KIFC1, KIFC2, KIFC3, KIN, KIR2DL1, KIR2DL2, KIR2DL3,KIR2DL4, KIR2DL5A, KIR2DL5B, KIR2DP1, KIR2DS1, KIR2DS2, KIR2DS3,KIR2DS4, KIR2DS5, KIR3DL1, KIR3DL2, KIR3DL3, KIR3DP1, KIR3DS1, KIR3DX1,KIRREL1, KIRREL2, KIRREL3, KISS1, KISS1R, KIT, KITLG, KIZ, KL, KLB,KLC1, KLC2, KLC3, KLC4, KLF1, KLF10, KLF11, KLF12, KLF13, KLF14, KLF15,KLF16, KLF17, KLF18, KLF2, KLF3, KLF4, KLF5, KLF6, KLF7, KLF8, KLF9,KLHDC1, KLHDC10, KLHDC2, KLHDC3, KLHDC4, KLHDC7A, KLHDC7B, KLHDC8A,KLHDC8B, KLHDC9, KLHL1, KLHL10, KLHL11, KLHL12, KLHL13, KLHL14, KLHL15,KLHL17, KLHL18, KLHL2, KLHL20, KLHL21, KLHL22, KLHL23, KLHL24, KLHL25,KLHL26, KLHL28, KLHL29, KLHL3, KLHL30, KLHL31, KLHL32, KLHL33, KLHL34,KLHL35, KLHL36, KLHL38, KLHL4, KLHL40, KLHL41, KLHL42, KLHL5, KLHL6,KLHL7, KLHL8, KLHL9, KLK1, KLK10, KLK11, KLK12, KLK13, KLK14, KLK15,KLK2, KLK3, KLK4, KLK5, KLK6, KLK7, KLK8, KLK9, KLKB1, KLLN, KLRB1,KLRC1, KLRC2, KLRC3, KLRC4, KLRC4-KLRK1, KLRD1, KLRF1, KLRF2, KLRG1,KLRG2, KLRK1, KMO, KMT2A, KMT2B, KMT2C, KMT2D, KMT2E, KMT5A, KMT5B,KMT5C, KNCN, KNDC1, KNG1, KNL1, KNOP1, KNSTRN, KNTC1, KP420437.1,KP420437.2, KP420437.3, KP420439.1, KP420440.1, KP420440.2, KP420440.3,KP420440.4, KP420440.5, KP420440.6, KP420440.7, KP420440.8, KP420440.9,KP420441.1, KP420441.2, KP420441.3, KP420441.4, KP420441.5, KP420442.2,KP420442.3, KP420443.1, KP420444.1, KP420444.2, KP420444.3, KP420444.4,KP420444.5, KP420444.6, KP420444.7, KP420446.1, KP420446.2, KPNA1,KPNA2, KPNA3, KPNA4, KPNA5, KPNA6, KPNA7, KPNB1, KPRP, KPTN, KRAS,KRBA1, KRBA2, KRBOX1, KRBOX4, KRCC1, KREMEN1, KREMEN2, KRI1, KRIT1,KRR1, KRT1, KRT10, KRT12, KRT13, KRT14, KRT15, KRT16, KRT17, KRT18,KRT19, KRT2, KRT20, KRT222, KRT23, KRT24, KRT25, KRT26, KRT27, KRT28,KRT3, KRT31, KRT32, KRT33A, KRT33B, KRT34, KRT35, KRT36, KRT37, KRT38,KRT39, KRT4, KRT40, KRT5, KRT6A, KRT6B, KRT6C, KRT7, KRT71, KRT72,KRT73, KRT74, KRT75, KRT76, KRT77, KRT78, KRT79, KRT8, KRT80, KRT81,KRT82, KRT83, KRT84, KRT85, KRT86, KRT9, KRTAP10-1, KRTAP10-10,KRTAP10-11, KRTAP10-12, KRTAP10-2, KRTAP10-3, KRTAP10-4, KRTAP10-5,KRTAP10-6, KRTAP10-7, KRTAP10-8, KRTAP10-9, KRTAP1-1, KRTAP11-1,KRTAP12-1, KRTAP12-2, KRTAP12-3, KRTAP12-4, KRTAP1-3, KRTAP13-1,KRTAP13-2, KRTAP13-3, KRTAP13-4, KRTAP1-4, KRTAP1-5, KRTAP15-1,KRTAP16-1, KRTAP17-1, KRTAP19-1, KRTAP19-2, KRTAP19-3, KRTAP19-4,KRTAP19-5, KRTAP19-6, KRTAP19-7, KRTAP19-8, KRTAP20-1, KRTAP20-2,KRTAP20-3, KRTAP20-4, KRTAP2-1, KRTAP21-1, KRTAP21-2, KRTAP21-3,KRTAP2-2, KRTAP22-1, KRTAP22-2, KRTAP2-3, KRTAP23-1, KRTAP2-4,KRTAP24-1, KRTAP25-1, KRTAP26-1, KRTAP27-1, KRTAP29-1, KRTAP3-1,KRTAP3-2, KRTAP3-3, KRTAP4-1, KRTAP4-11, KRTAP4-12, KRTAP4-16, KRTAP4-2,KRTAP4-3, KRTAP4-4, KRTAP4-5, KRTAP4-6, KRTAP4-7, KRTAP4-8, KRTAP4-9,KRTAP5-1, KRTAP5-10, KRTAP5-11, KRTAP5-2, KRTAP5-3, KRTAP5-4, KRTAP5-5,KRTAP5-6, KRTAP5-7, KRTAP5-8, KRTAP5-9, KRTAP6-1, KRTAP6-2, KRTAP6-3,KRTAP7-1, KRTAP8-1, KRTAP9-1, KRTAP9-2, KRTAP9-3, KRTAP9-4, KRTAP9-6,KRTAP9-7, KRTAP9-8, KRTAP9-9, KRTCAP2, KRTCAP3, KRTDAP, KSR1, KSR2,KTI12, KTN1, KU645196.1, KU645196.2, KU645196.3, KU645196.4, KU645196.5,KU645196.6, KU645196.7, KU645196.8, KU645196.9, KU645197.1, KU645197.2,KU645197.3, KU645197.4, KU645197.5, KU645198.1, KXD1, KY, KYAT1, KYAT3,KYNU, L1CAM, L1TD1, L2HGDH, L34079.1, L3HYPDH, L3MBTL1, L3MBTL2,L3MBTL3, L3MBTL4, LACC1, LACRT, LACTB, LACTB2, LACTBL1, LAD1, LAG3,LAGE3, LAIR1, LAIR2, LALBA, LAMA1, LAMA2, LAMA3, LAMA4, LAMA5, LAMB1,LAMB2, LAMB3, LAMB4, LAMC1, LAMC2, LAMC3, LAMP1, LAMP2, LAMP3, LAMP5,LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4, LAMTOR5, LANCL1, LANCL2, LANCL3,LAP3, LAPTM4A, LAPTM4B, LAPTM5, LARGE1, LARGE2, LARP1, LARP1B, LARP4,LARP4B, LARP6, LARP7, LARS, LARS2, LAS1L, LASP1, LAT, LAT2, LATS1,LATS2, LAX1, LAYN, LBH, LBHD1, LBP, LBR, LBX1, LBX2, LCA5, LCA5L, LCAT,LCE1A, LCE1B, LCE1C, LCE1D, LCE1E, LCE1F, LCE2A, LCE2B, LCE2C, LCE2D,LCE3A, LCE3B, LCE3C, LCE3D, LCE3E, LCE4A, LCE5A, LCE6A, LCK, LCLAT1,LCMT1, LCMT2, LCN1, LCN10, LCN12, LCN15, LCN2, LCN6, LCN8, LCN9, LCNL1,LCOR, LCORL, LCP1, LCP2, LCT, LCTL, LDAH, LDB1, LDB2, LDB3, LDHA,LDHAL6A, LDHAL6B, LDHB, LDHC, LDHD, LDLR, LDLRAD1, LDLRAD2, LDLRAD3,LDLRAD4, LDLRAP1, LDOC1, LEAP2, LECT2, LEF1, LEFTY1, LEFTY2, LEKR1,LELP1, LEMD1, LEMD2, LEMD3, LENEP, LENG1, LENG8, LENG9, LEO1, LEP, LEPR,LEPROT, LEPROTL1, LETM1, LETM2, LETMD1, LEUTX, LEXM, LFNG, LGALS1,LGALS12, LGALS13, LGALS14, LGALS16, LGALS2, LGALS3, LGALS3BP, LGALS4,LGALS7, LGALS7B, LGALS8, LGALS9, LGALS9B, LGALS9C, LGALSL, LGI1, LGI2,LGI3, LGI4, LGMN, LGR4, LGR5, LGR6, LGSN, LHB, LHCGR, LHFPL1, LHFPL2,LHFPL3, LHFPL4, LHFPL5, LHFPL6, LHPP, LHX1, LHX2, LHX3, LHX4, LHX5,LHX6, LHX8, LHX9, LIAS, LIF, LIFR, LIG1, LIG3, LIG4, LILRA1, LILRA2,LILRA3, LILRA4, LILRA5, LILRA6, LILRB1, LILRB2, LILRB3, LILRB4, LILRB5,LIM2, LIMA1, LIMCH1, LIMD1, LIMD2, LIME1, LIMK1, LIMK2, LIMS1, LIMS2,LIMS3, LIMS4, LIN28A, LIN28B, LIN37, LIN52, LIN54, LIN7A, LIN7B, LIN7C,LIN9, LINC00094, LINC00116, LINC00282, LINC00672, LINC00675, LINC00694,LINC00854, LINC00890, LINC00959, LINC01125, LINC01556, LINC02210-CRHR1,LINGO1, LINGO2, LINGO3, LINGO4, LINS1, LIPA, LIPC, LIPE, LIPF, LIPG,LIPH, LIPI, LIPJ, LIPK, LIPM, LIPN, LIPT1, LIPT2, LITAF, LIX1, LIX1L,LKAAEAR1, LLGL1, LLGL2, LLPH, LMAN1, LMAN1L, LMAN2, LMAN2L, LMBR1,LMBR1L, LMBRD1, LMBRD2, LMCD1, LMF1, LMF2, LMLN, LMNA, LMNB1, LMNB2,LMNTD1, LMNTD2, LMO1, LMO2, LMO3, LMO4, LMO7, LMO7DN, LMOD1, LMOD2,LMOD3, LMTK2, LMTK3, LMX1A, LMX1B, LNP1, LNPEP, LNPK, LNX1, LNX2,LO000005.1, LONP1, LONP2, LONRF1, LONRF2, LONRF3, LOR, LOX, LOXHD1,LOXL1, LOXL2, LOXL3, LOXL4, LPA, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5,LPAR6, LPCAT1, LPCAT2, LPCAT3, LPCAT4, LPGAT1, LPIN1, LPIN2, LPIN3, LPL,LPO, LPP, LPXN, LRAT, LRBA, LRCH1, LRCH2, LRCH3, LRCH4, LRCOL1, LRFN1,LRFN2, LRFN3, LRFN4, LRFN5, LRG1, LRGUK, LRIF1, LRIG1, LRIG2, LRIG3,LRIT1, LRIT2, LRIT3, LRMDA, LRMP, LRP1, LRP10, LRP11, LRP12, LRP1B,LRP2, LRP2BP, LRP3, LRP4, LRP5, LRP5L, LRP6, LRP8, LRPAP1, LRPPRC, LRR1,LRRC1, LRRC10, LRRC10B, LRRC14, LRRC14B, LRRC15, LRRC17, LRRC18, LRRC19,LRRC2, LRRC20, LRRC23, LRRC24, LRRC25, LRRC26, LRRC27, LRRC28, LRRC29,LRRC3, LRRC30, LRRC31, LRRC32, LRRC34, LRRC36, LRRC37A, LRRC37A2,LRRC37A3, LRRC37B, LRRC38, LRRC39, LRRC3B, LRRC3C, LRRC4, LRRC40,LRRC41, LRRC42, LRRC43, LRRC45, LRRC46, LRRC47, LRRC49, LRRC4B, LRRC4C,LRRC52, LRRC53, LRRC55, LRRC56, LRRC57, LRRC58, LRRC59, LRRC6, LRRC61,LRRC63, LRRC66, LRRC69, LRRC7, LRRC70, LRRC71, LRRC72, LRRC73, LRRC74A,LRRC74B, LRRC75A, LRRC75B, LRRC8A, LRRC8B, LRRC8C, LRRC8D, LRRC8E,LRRC9, LRRCC1, LRRD1, LRRFIP1, LRRFIP2, LRRIQ1, LRRIQ3, LRRIQ4, LRRK1,LRRK2, LRRN1, LRRN2, LRRN3, LRRN4, LRRN4CL, LRRTM1, LRRTM2, LRRTM3,LRRTM4, LRSAM1, LRTM1, LRTM2, LRTOMT, LRWD1, LSAMP, LSG1, LSM1, LSM10,LSM11, LSM12, LSM14A, LSM14B, LSM2, LSM3, LSM4, LSM5, LSM6, LSM7, LSM8,LSMEM1, LSMEM2, LSP1, LSR, LSS, LST1, LTA, LTA4H, LTB, LTB4R, LTB4R2,LTBP1, LTBP2, LTBP3, LTBP4, LTBR, LTC4S, LTF, LTK, LTN1, LTV1, LUC7L,LUC7L2, LUC7L3, LUM, LURAP1, LURAP1L, LUZP1, LUZP2, LUZP4, LUZP6, LVRN,LXN, LY6D, LY6E, LY6G5B, LY6G5C, LY6G6C, LY6G6D, LY6G6E, LY6G6F, LY6H,LY6K, LY6L, LY75, LY75-CD302, LY86, LY9, LY96, LYAR, LYG1, LYG2, LYL1,LYN, LYNX1, LYPD1, LYPD2, LYPD3, LYPD4, LYPD5, LYPD6, LYPD6B, LYPD8,LYPLA1, LYPLA2, LYPLAL1, LYRM1, LYRM2, LYRM4, LYRM7, LYRM9, LYSMD1,LYSMD2, LYSMD3, LYSMD4, LYST, LYVE1, LYZ, LYZL1, LYZL2, LYZL4, LYZL6,LZIC, LZTFL1, LZTR1, LZTS1, LZTS2, LZTS3, M1AP, M6PR, MAATS1, MAB21L1,MAB21L2, MAB21L3, MACC1, MACF1, MACROD1, MACROD2, MAD1L1, MAD2L1,MAD2L1BP, MAD2L2, MADCAM1, MADD, MAEA, MAEL, MAF, MAF1, MAFA, MAFB,MAFF, MAFG, MAFK, MAG, MAGEA1, MAGEA10, MAGEA11, MAGEA12, MAGEA2,MAGEA2B, MAGEA3, MAGEA4, MAGEA6, MAGEA8, MAGEA9, MAGEA9B, MAGEB1,MAGEB10, MAGEB16, MAGEB17, MAGEB18, MAGEB2, MAGEB3, MAGEB4, MAGEB5,MAGEB6, MAGEB6P1, MAGEC1, MAGEC2, MAGEC3, MAGED1, MAGED2, MAGED4,MAGED4B, MAGEE1, MAGEE2, MAGEF1, MAGEH1, MAGEL2, MAGI, MAGI, MAGI,MAGIX, MAGOH, MAGOHB, MAGT1, MAIP1, MAJIN, MAK, MAK16, MAL, MAL2, MALL,MALRD1, MALSU1, MALT1, MAMDC2, MAMDC4, MAML1, MAML2, MAML3, MAMLD1,MAMSTR, MAN1A1, MAN1A2, MAN1B1, MAN1C1, MAN2A1, MAN2A2, MAN2B1, MAN2B2,MAN2C1, MANBA, MANBAL, MANEA, MANEAL, MANF, MANSC1, MANSC4, MAOA, MAOB,MAP10, MAP1A, MAP1B, MAP1LC3A, MAP1LC3B, MAP1LC3B2, MAP1LC3C, MAP1S,MAP2, MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K5, MAP2K6, MAP2K7, MAP3K1,MAP3K10, MAP3K11, MAP3K12, MAP3K13, MAP3K14, MAP3K15, MAP3K19, MAP3K2,MAP3K20, MAP3K21, MAP3K3, MAP3K4, MAP3K5, MAP3K6, MAP3K7, MAP3K7CL,MAP3K8, MAP3K9, MAP4, MAP4K1, MAP4K2, MAP4K3, MAP4K4, MAP4K5, MAP6,MAP6D1, MAP7, MAP7D1, MAP7D2, MAP7D3, MAPS, MAPK1, MAPK10, MAPK11,MAPK12, MAPK13, MAPK14, MAPK15, MAPK1IP1L, MAPK3, MAPK4, MAPK6, MAPK7,MAPK8, MAPK8IP1, MAPK8IP2, MAPK8IP3, MAPK9, MAPKAP1, MAPKAPK2, MAPKAPK3,MAPKAPK5, MAPKBP1, MAPRE1, MAPRE2, MAPRE3, MAPT, MARC1, MARC2, MARCH1,MARCH10, MARCH11, MARCH2, MARCH3, MARCH4, MARCH5, MARCH6, MARCH7,MARCH8, MARCH9, MARCKS, MARCKSL1, MARCO, MARF1, MARK1, MARK2, MARK3,MARK4, MARS, MARS2, MARVELD 1, MARVELD2, MARVELD3, MAS1, MAS1L, MASP1,MASP2, MAST1, MAST2, MAST3, MAST4, MASTL, MAT1A, MAT2A, MAT2B, MATK,MATN1, MATN2, MATN3, MATN4, MATR3, MAU2, MAVS, MAX, MAZ, MB, MB21D1,MB21D2, MBD1, MBD2, MBD3, MBD3L1, MBD3L2, MBD3L2B, MBD3L3, MBD3L4,MBD3L5, MBD4, MBD5, MBD6, MBIP, MBL2, MBLAC1, MBLAC2, MBNL1, MBNL2,MBNL3, MBOAT1, MBOAT2, MBOAT4, MBOAT7, MBP, MBTD1, MBTPS1, MBTPS2, MC1R,MC2R, MC3R, MC4R, MC5R, MCAM, MCAT, MCC, MCCC1, MCCC2, MCCD1, MCEE,MCEMP1, MCF2, MCF2L, MCF2L2, MCFD2, MCHR1, MCHR2, MCIDAS, MCL1, MCM10,MCM2, MCM3, MCM3AP, MCM4, MCM5, MCM6, MCMI, MCM8, MCM9, MCMBP, MCMDC2,MCOLN1, MCOLN2, MCOLN3, MCPH1, MCRIP1, MCRIP2, MCRS1, MCTP1, MCTP2,MCTS1, MCU, MCUB, MCUR1, MDC1, MDFI, MDFIC, MDFIC2, MDGA1, MDGA2, MDH1,MDH1B, MDH2, MDK, MDM1, MDM2, MDM4, MDN1, MDP1, MDS2, ME1, ME2, ME3,MEA1, MEAF6, MECOM, MECP2, MECR, MED1, MED10, MED11, MED12, MED12L,MED13, MED13L, MED14, MED14OS, MED15, MED16, MED17, MED18, MED19, MED20,MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED28, MED29, MED30,MED31, MED4, MED6, MED7, MED8, MED9, MEDAG, MEF2A, MEF2B, MEF2C, MEF2D,MEFV, MEGF10, MEGF11, MEGF6, MEGF8, MEGF9, MEI1, MEI4, MEIG1, MEIKIN,MEIOB, MEIOC, MEIS1, MEIS2, MEIS3, MELK, MELTF, MEMO1, MEN1, MEOX1,MEOX2, MEP1A, MEP1B, MEPCE, MEPE, MERTK, MESD, MESP1, MESP2, MEST, MET,METAP1, METAP1D, METAP2, METRN, METRNL, METTL1, METTL11B, METTL12,METTL13, METTL14, METTL15, METTL16, METTL17, METTL18, METTL21A,METTL21C, METTL22, METTL23, METTL24, METTL25, METTL26, METTL27, METTL2A,METTL2B, METTL3, METTL4, METTL5, METTL6, METTL7A, METTL7B, METTL8,METTL9, MEX3A, MEX3B, MEX3C, MEX3D, MFAP1, MFAP2, MFAP3, MFAP3L, MFAP4,MFAP5, MFF, MFGE8, MFHAS1, MFN1, MFN2, MFNG, MFRP, MFSD1, MFSD10,MFSD11, MFSD12, MFSD13A, MFSD14A, MFSD14B, MFSD14C, MFSD2A, MFSD2B,MFSD3, MFSD4A, MFSD4B, MFSD5, MFSD6, MFSD6L, MFSD7, MFSD8, MFSD9, MGA,MGAM, MGAM2, MGARP, MGAT1, MGAT2, MGAT3, MGAT4A, MGAT4B, MGAT4C, MGAT4D,MGAT5, MGAT5B, MGEA5, MGLL, MGME1, MGMT, MGP, MGRN1, MGST1, MGST2,MGST3, MIA, MIA3, MIA-RAB4B, MIB1, MIB2, MICA, MICAL1, MICAL2, MICAL3,MICALCL, MICALL1, MICALL2, MICB, MICU1, MICU2, MICU3, MID1, MID1IP1,MID2, MIDN, MIEF1, MIEF2, MIEN1, MIER1, MIER2, MIER3, MIF, MIF4GD,MIGA1, MIGA2, MIIP, MILR1, MINDY1, MINDY2, MINDY3, MINDY4, MINDY4B,MINK1, MINOS1, MINOS1-NBL1, MINPP1, MIOS, MIOX, MIP, MIPEP, MIPOL1,MIS12, MIS18A, MIS18BP1, MISP, MISP3, MITD1, MITF, MIXL1, MKI67, MKKS,MKL1, MKL2, MKLN1, MKNK1, MKNK2, MKRN1, MKRN2, MKRN2OS, MKRN3, MKS1,MKX, MLANA, MLC1, MLEC, MLF1, MLF2, MLH1, MLH3, MLIP, MLKL, MLLT1,MLLT10, MLLT11, MLLT3, MLLT6, MLN, MLNR, MLPH, MLST8, MLX, MLXIP,MLXIPL, MLYCD, MMAA, MMAB, MMACHC, MMADHC, MMD, MMD2, MME, MMEL1, MMGT1, MMP 1, MMP 10, MMP 11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17,MMP19, MMP2, MMP20, MMP21, MMP23B, MMP24, MMP24-AS1, MMP25, MMP26,MMP27, MMP28, MMP3, MMP7, MMP8, MMP9, MMRN1, MMRN2, MMS19, MMS22L, MN1,MNAT1, MND1, MNDA, MNS1, MNT, MNX1, MOAP1, MOB1A, MOB1B, MOB2, MOB3A,MOB3B, MOB3C, MOB4, MOBP, MOCOS, MOCS1, MOCS2, MOCS3, MOG, MOGAT1,MOGAT2, MOGAT3, MOGS, MOK, MON1A, MON1B, MON2, MORC1, MORC2, MORC3,MORC4, MORF4L1, MORF4L2, MORN1, MORN2, MORN3, MORN4, MORN5, MOS, MOSPD1,MOSPD2, MOSPD3, MOV10, MOV10L1, MOXD1, MPC1, MPC1L, MPC2, MPDU1, MPDZ,MPEG1, MPG, MPHOSPH10, MPHOSPH6, MPHOSPH8, MPHOSPH9, MPI, MPIG6B, MPL,MPLKIP, MPND, MPO, MPP1, MPP2, MPP3, MPP4, MPP5, MPP6, MPP7, MPPE1,MPPED1, MPPED2, MPRIP, MPST, MPV17, MPV17L, MPV17L2, MPZ, MPZL1, MPZL2,MPZL3, MR1, MRAP, MRAP2, MRAS, MRC1, MRC2, MRE11, MREG, MRFAP1,MRFAP1L1, MRGBP, MRGPRD, MRGPRE, MRGPRF, MRGPRG, MRGPRX1, MRGPRX2,MRGPRX3, MRGPRX4, MRI1, MRLN, MRM1, MRM2, MRM3, MRNIP, MRO, MROH1,MROH2A, MROH2B, MROH5, MROH6, MROH7, MROH7-TTC4, MROH8, MROH9, MRPL1,MRPL10, MRPL11, MRPL12, MRPL13, MRPL14, MRPL15, MRPL16, MRPL17, MRPL18,MRPL19, MRPL2, MRPL20, MRPL21, MRPL22, MRPL23, MRPL24, MRPL27, MRPL28,MRPL3, MRPL30, MRPL32, MRPL33, MRPL34, MRPL35, MRPL36, MRPL37, MRPL38,MRPL39, MRPL4, MRPL40, MRPL41, MRPL42, MRPL43, MRPL44, MRPL45, MRPL46,MRPL47, MRPL48, MRPL49, MRPL50, MRPL51, MRPL52, MRPL53, MRPL54, MRPL55,MRPL57, MRPL58, MRPL9, MRPS10, MRPS11, MRPS12, MRPS14, MRPS15, MRPS16,MRPS17, MRPS18A, MRPS18B, MRPS18C, MRPS2, MRPS21, MRPS22, MRPS23,MRPS24, MRPS25, MRPS26, MRPS27, MRPS28, MRPS30, MRPS31, MRPS33, MRPS34,MRPS35, MRPS36, MRPS5, MRPS6, MRPS7, MRPS9, MRRF, MRS2, MRTO4, MRVI1,MS4A1, MS4A10, MS4A12, MS4A13, MS4A14, MS4A15, MS4A2, MS4A3, MS4A4A,MS4A4E, MS4A5, MS4A6A, MS4A6E, MS4A7, MS4A8, MSANTD1, MSANTD2, MSANTD3,MSANTD3-TMEFF1, MSANTD4, MSC, MSGN1, MSH2, MSH3, MSH4, MSH5,MSH5-SAPCD1, MSH6, MSI1, MSI2, MSL1, MSL2, MSL3, MSLN, MSLNL, MSMB,MSMO1, MSMP, MSN, MSR1, MSRA, MSRB1, MSRB2, MSRB3, MSS51, MST1, MST1R,MSTN, MSTO1, MSX1, MSX2, MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1HL1,MT1M, MT1X, MT2A, MT3, MT4, MTA1, MTA2, MTA3, MTAP, MT-ATP6, MT-ATP8,MTBP, MTCH1, MTCH2, MTCL1, MT-CO1, MT-CO2, MT-CO3, MTCP1, MT-CYB, MTDH,MTERF1, MTERF2, MTERF3, MTERF4, MTF1, MTF2, MTFMT, MTFP1, MTFR1, MTFR1L,MTFR2, MTG1, MTG2, MTHFD1, MTHFD1L, MTHFD2, MTHFD2L, MTHFR, MTHFS,MTHFSD, MTIF2, MTIF3, MTM1, MTMR1, MTMR10, MTMR11, MTMR12, MTMR14,MTMR2, MTMR3, MTMR4, MTMR6, MTMR7, MTMR8, MTMR9, MT-ND1, MT-ND2, MT-ND3,MT-ND4, MT-ND4L, MT-ND5, MT-ND6, MTNR1A, MTNR1B, MTO1, MTOR, MTPAP,MTPN, MTR, MTRF1, MTRF1L, MTRNR2L1, MTRNR2L10, MTRNR2L11, MTRNR2L12,MTRNR2L13, MTRNR2L3, MTRNR2L4, MTRNR2L5, MTRNR2L6, MTRNR2L7, MTRNR2L8,MTRR, MTSS1, MTSS1L, MTTP, MTURN, MTUS1, MTUS2, MTX1, MTX2, MTX3, MUC1,MUC12, MUC13, MUC15, MUC16, MUC17, MUC2, MUC20, MUC21, MUC22, MUC3A,MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUCL1, MUL1, MUM1, MUM1L1, MUS81, MUSK,MUSTN1, MUT, MUTYH, MVB12A, MVB12B, MVD, MVK, MVP, MX1, MX2, MXD1, MXD3,MXD4, MXI1, MXRA5, MXRA7, MXRA8, MYADM, MYADML2, MYB, MYBBP1A, MYBL1,MYBL2, MYBPC1, MYBPC2, MYBPC3, MYBPH, MYBPHL, MYC, MYCBP, MYCBP2,MYCBPAP, MYCL, MYCN, MYCT1, MYD88, MYDGF, MYEF2, MYEOV, MYF5, MYF6,MYH1, MYH10, MYH11, MYH13, MYH14, MYH15, MYH2, MYH3, MYH4, MYH6, MYH7,MYH7B, MYH8, MYH9, MYL1, MYL10, MYL12A, MYL12B, MYL2, MYL3, MYL4, MYL5,MYL6, MYL6B, MYL7, MYL9, MYLIP, MYLK, MYLK2, MYLK3, MYLK4, MYLPF, MYMK,MYMX, MYNN, MYO10, MYO15A, MYO15B, MYO16, MYO18A, MYO18B, MYO19, MYO1A,MYO1B, MYO1C, MYO1D, MYO1E, MYO1F, MYO1G, MYO1H, MYO3A, MYO3B, MYO5A,MYO5B, MYO5C, MYO6, MYO7A, MYO7B, MYO9A, MYO9B, MYOC, MYOCD, MYOCOS,MYOD1, MYOF, MYOG, MYOM1, MYOM2, MYOM3, MYOT, MYOZ1, MYOZ2, MYOZ3, MYPN,MYPOP, MYRF, MYRFL, MYRIP, MYSM1, MYT1, MYT1L, MYZAP, MZB1, MZF 1, MZT1,MZT2A, MZT2B, N4BP1, N4BP2, N4BP2L1, N4BP2L2, N4BP3, N6AMT1, NAA10,NAA11, NAA15, NAA16, NAA20, NAA25, NAA30, NAA35, NAA38, NAA40, NAA50,NAA60, NAAA, NAALAD2, NAALADL1, NAALADL2, NAB1, NAB2, NABP1, NABP2,NACA, NACA2, NACAD, NACC1, NACC2, NADK, NADK2, NADSYN1, NAE1, NAF1,NAGA, NAGK, NAGLU, NAGPA, NAGS, NAIF1, NAIP, NALCN, NAMPT, NANOG,NANOGNB, NANOGP8, NANOS1, NANOS2, NANOS3, NANP, NANS, NAP1L1, NAP1L2,NAP1L3, NAP1L4, NAP1L5, NAPA, NAPB, NAPEPLD, NAPG, NAPRT, NAPSA, NARF,NARFL, NARS, NARS2, NASP, NAT 1, NAT 10, NAT14, NAT16, NAT2, NAT6, NAT8,NAT8B, NAT8L, NAT9, NATD1, NAV1, NAV2, NAV3, NAXD, NAXE, NBAS, NBDY,NBEA, NBEAL1, NBEAL2, NBL1, NBN, NBPF 1, NBPF 10, NBPF11, NBPF 12,NBPF14, NBPF15, NBPF19, NBPF20, NBPF26, NBPF3, NBPF4, NBPF6, NBPF9,NBR1, NCALD, NCAM1, NCAM2, NCAN, NCAPD2, NCAPD3, NCAPG, NCAPG2, NCAPH,NCAPH2, NCBP1, NCBP2, NCBP2-AS2, NCBP2L, NCBP3, NCCRP1, NCDN, NCEH1,NCF1, NCF2, NCF4, NCK1, NCK2, NCKAP1, NCKAP1L, NCKAP5, NCKAP5L, NCKIPSD,NCL, NCLN, NCMAP, NCOA1, NCOA2, NCOA3, NCOA4, NCOA5, NCOA6, NCOA7,NCOR1, NCOR2, NCR1, NCR2, NCR3, NCR3LG1, NCS1, NCSTN, NDC1, NDC80, NDE1,NDEL1, NDFIP1, NDFIP2, NDN, NDNF, NDOR1, NDP, NDRG1, NDRG2, NDRG3,NDRG4, NDST1, NDST2, NDST3, NDST4, NDUFA1, NDUFA10, NDUFA11, NDUFA12,NDUFA13, NDUFA2, NDUFA3, NDUFA4, NDUFA4L2, NDUFA5, NDUFA6, NDUFA7,NDUFA8, NDUFA9, NDUFAB1, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5,NDUFAF6, NDUFAF7, NDUFAF8, NDUFB1, NDUFB10, NDUFB11, NDUFB2, NDUFB3,NDUFB4, NDUFB5, NDUFB6, NDUFB7, NDUFB8, NDUFB9, NDUFC1, NDUFC2,NDUFC2-KCTD14, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS5, NDUFS6, NDUFS7,NDUFS8, NDUFV1, NDUFV2, NDUFV3, NEB, NEBL, NECAB1, NECAB2, NECAB3,NECAP1, NECAP2, NECTIN1, NECTIN2, NECTIN3, NECTIN4, NEDD1, NEDD4,NEDD4L, NEDD8, NEDD8-MDP1, NEDD9, NEFH, NEFL, NEFM, NEGR1, NEIL 1,NEIL2, NEIL3, NEK1, NEK10, NEK11, NEK2, NEK3, NEK4, NEK5, NEK6, NEK7,NEK8, NEK9, NELFA, NELFB, NELFCD, NELFE, NELL1, NELL2, NEMF, NEMP1,NEMP2, NENF, NEO1, NEPRO, NES, NET1, NETO1, NETO2, NEU1, NEU2, NEU3,NEU4, NEURL1, NEURL1B, NEURL2, NEURL3, NEURL4, NEUROD1, NEUROD2,NEUROD4, NEUROD6, NEUROG1, NEUROG2, NEUROG3, NEXMIF, NEXN, NF1, NF2,NFAM1, NFASC, NFAT5, NFATC1, NFATC2, NFATC2IP, NFATC3, NFATC4, NFE2,NFE2L1, NFE2L2, NFE2L3, NFE4, NFIA, NFIB, NFIC, NFIL3, NFIX, NFKB1,NFKB2, NFKBIA, NFKBIB, NFKBID, NFKBIE, NFKBILL NFKBIZ, NFRKB, NFS1,NFU1, NFX1, NFXL1, NFYA, NFYB, NFYC, NGB, NGDN, NGEF, NGF, NGFR, NGLY1,NGRN, NHEJ1, NHLH1, NHLH2, NHLRC1, NHLRC2, NHLRC3, NHLRC4, NHP2, NHS,NHSL1, NHSL2, NICN1, NID1, NID2, NIF3L1, NIFK, NIM1K, NIN, NINJ1, NINJ2,NINL, NIP7, NIPA1, NIPA2, NIPAL1, NIPAL2, NIPAL3, NIPAL4, NIPBL,NIPSNAP1, NIPSNAP2, NIPSNAP3A, NIPSNAP3B, NISCH, NIT1, NIT2, NKAIN1,NKAIN2, NKAIN3, NKAIN4, NKAP, NKAPL, NKD1, NKD2, NKG7, NKIRAS1, NKIRAS2,NKPD1, NKRF, NKTR, NKX1-1, NKX1-2, NKX2-1, NKX2-2, NKX2-3, NKX2-4,NKX2-5, NKX2-6, NKX2-8, NKX1-1, NKX3-2, NKX6-1, NKX6-2, NKX6-3, NLE1,NLGN1, NLGN2, NLGN3, NLGN4X, NLGN4Y, NLK, NLN, NLRC3, NLRC4, NLRC5,NLRP1, NLRP10, NLRP11, NLRP12, NLRP13, NLRP14, NLRP2, NLRP2B, NLRP3,NLRP4, NLRP5, NLRP6, NLRP7, NLRP8, NLRP9, NLRX1, NMB, NMBR, NMD3, NME1,NME1-NME2, NME2, NME3, NME4, NME5, NME6, NME7, NME8, NME9, NMI, NMNAT1,NMNAT2, NMNAT3, NMRAL1, NMRK1, NMRK2, NMS, NMT1, NMT2, NMU, NMUR1,NMUR2, NNAT, NNMT, NNT, NOA1, NOB1, NOBOX, NOC2L, NOC3L, NOC4L, NOCT,NOD1, NOD2, NODAL, NOG, NOL10, NOL11, NOL12, NOL3, NOL4, NOL4L, NOL6,NOL7, NOL8, NOL9, NOLC 1, NOM1, NOMO1, NOMO2, NOMO3, NONO, NOP10, NOP14,NOP16, NOP2, NOP53, NOP56, NOP58, NOP9, NOS1, NOS1AP, NOS2, NOS3, NOSIP,NOSTRIN, NOTCH1, NOTCH2, NOTCH2NL, NOTCH3, NOTCH4, NOTO, NOTUM, NOV,NOVA1, NOVA2, NOX1, NOX3, NOX4, NOX5, NOXA1, NOXO1, NOXRED1, NPAP1,NPAS1, NPAS2, NPAS3, NPAS4, NPAT, NPB, NPBWR1, NPBWR2, NPC1, NPC1L1,NPC2, NPDC1, NPEPL1, NPEPPS, NPFF, NPFFR1, NPFFR2, NPHP1, NPHP3,NPHP3-ACAD11, NPHP4, NPHS1, NPHS2, NPIPA1, NPIPA2, NPIPA3, NPIPA5,NPIPA7, NPIPA8, NPIPB11, NPIPB12, NPIPB13, NPIPB15, NPIPB2, NPIPB3,NPIPB4, NPIPB5, NPIPB6, NPIPB7, NPIPB8, NPIPB9, NPL, NPLOC4, NPM1, NPM2,NPM3, NPNT, NPPA, NPPB, NPPC, NPR1, NPR2, NPR3, NPRL2, NPRL3, NPS,NPSR1, NPTN, NPTX1, NPTX2, NPTXR, NPVF, NPW, NPY, NPY1R, NPY2R, NPY4R,NPY4R2, NPY5R, NQO1, NQO2, NROB1, NROB2, NR1D1, NR1D2, NR1H2, NR1H3,NR1H4, NR1I2, NR1I3, NR2C1, NR2C2, NR2C2AP, NR2E1, NR2E3, NR2F1, NR2F2,NR2F6, NR3C1, NR3C2, NR4A1, NR4A2, NR4A3, NR5A1, NR5A2, NR₆A1, NRAP,NRARP, NRAS, NRBF2, NRBP1, NRBP2, NRCAM, NRDC, NRDE2, NREP, NRF 1, NRG1,NRG2, NRG3, NRG4, NRGN, NRIP 1, NRIP2, NRIP3, NRK, NRL, NRM, NRN1,NRN1L, NRP1, NRP2, NRROS, NRSN1, NRSN2, NRTN, NRXN1, NRXN2, NRXN3, NSA2,NSD1, NSD2, NSD3, NSDHL, NSF, NSFL1C, NSL1, NSMAF, NSMCE1, NSMCE2,NSMCE3, NSMCE4A, NSMF, NSRP1, NSUN2, NSUN3, NSUN4, NSUN5, NSUN6, NSUN7,NT5C, NT5C1A, NT5C1B, NT5C1B-RDH14, NT5C2, NT5C3A, NT5C3B, NT5DC1,NT5DC2, NT5DC3, NT5DC4, NT5E, NT5M, NTAN1, NTF3, NTF4, NTHL1, NTM,NTMT1, NTN1, NTN3, NTN4, NTN5, NTNG1, NTNG2, NTPCR, NTRK1, NTRK2, NTRK3,NTS, NTSR1, NTSR2, NUAK1, NUAK2, NUB1, NUBP1, NUBP2, NUBPL, NUCB1,NUCB2, NUCKS1, NUDC, NUDCD1, NUDCD2, NUDCD3, NUDT1, NUDT10, NUDT11,NUDT12, NUDT13, NUDT14, NUDT15, NUDT16, NUDT16L1, NUDT17, NUDT18,NUDT19, NUDT2, NUDT21, NUDT22, NUDT3, NUDT4, NUDT4P1, NUDT5, NUDT6,NUDT7, NUDT8, NUDT9, NUF2, NUFIP1, NUFIP2, NUGGC, NUMA1, NUMB, NUMBL,NUP107, NUP133, NUP153, NUP155, NUP160, NUP188, NUP205, NUP210, NUP210L,NUP214, NUP35, NUP37, NUP43, NUP50, NUP54, NUP58, NUP62, NUP62CL, NUP85,NUP88, NUP93, NUP98, NUPL2, NUPR1, NUPR2, NUS1, NUSAP1, NUTF2, NUTM1,NUTM2A, NUTM2B, NUTM2D, NUTM2E, NUTM2F, NUTM2G, NVL, NWD1, NWD2, NXF1,NXF2, NXF2B, NXF3, NXF5, NXN, NXNL1, NXNL2, NXPE1, NXPE2, NXPE3, NXPE4,NXPH1, NXPH2, NXPH3, NXPH4, NXT 1, NXT2, NYAP 1, NYAP2, NYNRIN, NYX,OAF, OARD1, OAS1, OAS2, OAS3, OASL, OAT, OAZ1, OAZ2, OAZ3, OBP2A, OBP2B,OBSCN, OBSCN-AS1, OBSL1, OC90, OCA2, OCEL1, OCIAD1, OCIAD2, OCLM, OCLN,OCM, OCM2, OCRL, OCSTAMP, ODAM, ODC1, ODF1, ODF2, ODF2L, ODF3, ODF3B,ODF3L1, ODF3L2, ODF4, OFCC1, OFD1, OGDH, OGDHL, OGFOD1, OGFOD2, OGFOD3,OGFR, OGFRL1, OGG1, OGN, OGT, OIP5, OIT3, OLA1, OLAH, OLFM1, OLFM2,OLFM3, OLFM4, OLFML1, OLFML2A, OLFML2B, OLFML3, OLIG1, OLIG2, OLIG3,OLR1, OMA1, OMD, OMG, OMP, ONECUT1, ONECUT2, ONECUT3, OOEP, OOSP2, OPA1,OPA3, OPALIN, OPCML, OPHN1, OPLAH, OPN1LW, OPN1MW, OPN1MW2, OPN1MW3,OPN1SW, OPN3, OPN4, OPN5, OPRD1, OPRK1, OPRL1, OPRM1, OPRPN, OPTC, OPTN,OR10A2, OR10A3, OR10A4, OR10A5, OR10A6, OR10A7, OR10AC1, OR10AD1,OR10AG1, OR10C1, OR10D3, OR10G2, OR10G3, OR10G4, OR10G6, OR10G7, OR10G8,OR10G9, OR10H1, OR10H2, OR10H3, OR10H4, OR10E15, OR10J1, OR10J3, OR10J4,OR10J5, OR1OK 1, OR10K2, OR10P1, OR10Q1, OR1OR2, OR10S1, OR10T2, OR10V1,OR10W1, OR10X1, OR10Z1, OR11A1, OR11G2, OR11H1, OR11H12, OR11H2, OR11H4,OR11H6, OR11H7, OR11L1, OR12D1, OR12D2, OR12D3, OR13A1, OR13C2, OR13C3,OR13C4, OR13C5, OR13C7, OR13C8, OR13C9, OR13D1, OR13F1, OR13G1, OR13H1,OR13J1, OR14A16, OR14A2, OR14C36, OR1411, OR14J1, OR14K1, OR1A1, OR1A2,OR1B1, OR1C1, OR1D2, OR1D5, OR1E1, OR1E2, OR1F1, OR1G1, OR1I1, OR1J1,OR1J2, OR1J4, OR1K1, OR1L1, OR1L3, OR1L4, OR1L6, OR1L8, OR1M1, OR1N1,OR1N2, OR1P1, OR1Q1, OR1S1, OR1S2, OR2A1, OR2A12, OR2A14, OR2A2, OR2A25,OR2A4, OR2A42, OR2A5, OR2A7, OR2AE1, OR2AG1, OR2AG2, OR2AJ1, OR2AK2,OR2AP1, OR2AT4, OR2B11, OR2B2, OR2B3, OR2B6, OR2C1, OR2C3, OR2D2, OR2D3,OR2F1, OR2F2, OR2G2, OR2G3, OR2G6, OR2H1, OR2H2, OR2J1, OR2J2, OR2J3,OR2K2, OR2L13, OR2L2, OR2L3, OR2L5, OR2L8, OR2M2, OR2M3, OR2M4, OR2M5,OR2M7, OR2S2, OR2T1, OR2T10, OR2T11, OR2T12, OR2T2, OR2T27, OR2T29,OR2T3, OR2T33, OR2T34, OR2T35, OR2T4, OR2T5, OR2T6, OR2T7, OR2T8, OR2V1,OR2V2, OR2W1, OR2W3, OR2Y1, OR2Z1, OR3A1, OR3A2, OR3A3, OR4A15, OR4A16,OR4A47, OR4A5, OR4A8, OR4B1, OR4C11, OR4C12, OR4C13, OR4C15, OR4C16,OR4C3, OR4C45, OR4C46, OR4C5, OR4C6, OR4D1, OR4D10, OR4D11, OR4D2,OR4D5, OR4D6, OR4D9, OR4E1, OR4E2, OR4F15, OR4F16, OR4F17, OR4F21,OR4F29, OR4F3, OR4F4, OR4F5, OR4F6, OR4K1, OR4K13, OR4K14, OR4K15,OR4K17, OR4K2, OR4K3, OR4K5, OR4L1, OR4M1, OR4M2, OR4N2, OR4N4, OR4N5,OR4P4, OR4Q2, OR4Q3, OR4S1, OR4S2, OR4X1, OR4X2, OR51A2, OR51A4, OR51A7,OR51B2, OR51B4, OR51B5, OR51B6, OR51D1, OR51E1, OR51E2, OR51F1, OR51F2,OR51G1, OR51G2, OR51H1, OR51I1, OR51I2, OR51J1, OR51L1, OR51M1, OR51Q1,OR51S1, OR51T1, OR51V1, OR52A1, OR52A5, OR52B2, OR52B4, OR52B6, OR52D1,OR52E2, OR52E4, OR52E5, OR52E6, OR52E8, OR52H1, OR5211, OR5212, OR52J3,OR52K1, OR52K2, OR52L1, OR52M1, OR52N1, OR52N2, OR52N4, OR52N5, OR52R1,OR52W1, OR52Z1, OR56A1, OR56A3, OR56A4, OR56A5, OR56B1, OR56B4, OR5A1,OR5A2, OR5AC1, OR5AC2, OR5AK2, OR5AN1, OR5AP2, OR5AR1, OR5AS1, OR5AU1,OR5B12, OR5B17, OR5B2, OR5B21, OR5B3, OR5C1, OR5D13, OR5D14, OR5D16,OR5D18, OR5F1, OR5G3, OR5H1, OR5H14, OR5H15, OR5H2, OR5H6, OR5H8, OR5I1,OR5J2, OR5K1, OR5K2, OR5K3, OR5K4, OR5L1, OR5L2, OR5M1, OR5M10, OR5M11,OR5M3, OR5M8, OR5M9, OR5P2, OR5P3, OR5R1, OR5T1, OR5T2, OR5T3, OR5V1,OR5W2, OR6A2, OR6B1, OR6B2, OR6B3, OR6C1, OR6C2, OR6C3, OR6C4, OR6C6,OR6C65, OR6C68, OR6C70, OR6C74, OR6C75, OR6C76, OR6F1, OR6J1, OR6K2,OR6K3, OR6K6, OR6M1, OR6N1, OR6N2, OR6P1, OR6Q1, OR6S1, OR6T1, OR6V1,OR6X1, OR6Y1, OR7A10, OR7A17, OR7A5, OR7C1, OR7C2, OR7D2, OR7D4, OR7E24,OR7G1, OR7G2, OR7G3, OR8A1, OR8B12, OR8B2, OR8B3, OR8B4, OR8B8, OR8D1,OR8D2, OR8D4, OR8G1, OR8G5, OR8H1, OR8H2, OR8H3, OR812, OR8J1, OR8J2,OR8J3, OR8K1, OR8K3, OR8K5, OR8S1, OR8U1, OR8U8, OR9A2, OR9A4, OR9G1,OR9G4, OR9G9, OR9H1P, OR9I1, OR9K2, OR9Q1, OR9Q2, ORAI1, ORAI2, ORAI3,ORAOV1, ORC1, ORC2, ORC3, ORC4, ORC5, ORC6, ORM1, ORM2, ORMDL1, ORMDL2,ORMDL3, OS9, OSBP, OSBP2, OSBPL10, OSBPL11, OSBPL1A, OSBPL2, OSBPL3,OSBPL5, OSBPL6, OSBPL7, OSBPL8, OSBPL9, OSCAR, OSCP1, OSER1, OSGEP,OSGEPL1, OSGIN1, OSGIN2, OSM, OSMR, OSR1, OSR2, OST4, OSTC, OSTF1,OSTM1, OSTN, OTC, OTOA, OTOF, OTOG, OTOGL, OTOL1, OTOP1, OTOP2, OTOP3,OTOR, OTOS, OTP, OTUB1, OTUB2, OTUD1, OTUD3, OTUD4, OTUD5, OTUD6A,OTUD6B, OTUD7A, OTUD7B, OTULIN, OTX1, OTX2, OVCA2, OVCH1, OVCH2, OVGP1,OVOL1, OVOL2, OVOL3, OXA1L, OXCT1, OXCT2, OXER1, OXGR1, OXLD1, OXNAD1,OXR1, OXSM, OXSR1, OXT, OXTR, P2RX1, P2RX2, P2RX3, P2RX4, P2RX5,P2RX5-TAX1BP3, P2RX6, P2RX7, P2RY1, P2RY10, P2RY11, P2RY12, P2RY13,P2RY14, P2RY2, P2RY4, P2RY6, P2RY8, P3H1, P3H2, P3H3, P3H4, P4HA1,P4HA2, P4HA3, P4HB, P4HTM, PA2G4, PAAF1, PABPC1, PABPC1L, PABPC1L2A,PABPC1L2B, PABPC3, PABPC4, PABPC4L, PABPC5, PABPN1, PABPN1L, PACRG,PACRGL, PACS1, PACS2, PACSIN1, PACSIN2, PACSIN3, PADI1, PADI2, PADI3,PADI4, PADI6, PAEP, PAF1, PAFAH1B1, PAFAH1B2, PAFAH1B3, PAFAH2, PAG1,PAGE1, PAGE2, PAGE2B, PAGE3, PAGE4, PAGES, PAGR1, PAH, PAICS, PAIP1,PAIP2, PAIP2B, PAK1, PAK1IP1, PAK2, PAK3, PAK4, PAK5, PAK6, PALB2,PALD1, PALLD, PALM, PALM2, PALM2-AKAP2, PALM3, PALMD, PAM, PAM16, PAMR1,PAN2, PAN3, PANK1, PANK2, PANK3, PANK4, PANO1, PANX1, PANX2, PANX3,PAOX, PAPD4, PAPD5, PAPD7, PAPLN, PAPOLA, PAPOLB, PAPOLG, PAPPA, PAPPA2,PAPSS1, PAPSS2, PAQR3, PAQR4, PAQR5, PAQR6, PAQR7, PAQR8, PAQR9, PARD3,PARD3B, PARD6A, PARD6B, PARD6G, PARG, PARK7, PARL, PARM1, PARN, PARP1,PARP10, PARP11, PARP12, PARP14, PARP15, PARP16, PARP2, PARP3, PARP4,PARP6, PARP8, PARP9, PARPBP, PARS2, PARVA, PARVB, PARVG, PASD1, PASK,PATE1, PATE2, PATE3, PATE4, PATJ, PATL1, PATL2, PATZ1, PAWR, PAX1, PAX2,PAX3, PAX4, PAX5, PAX6, PAX7, PAX8, PAX9, PAXBP1, PAXIP1, PAXX, PBDC1,PBK, PBLD, PBOV1, PBRM1, PBX1, PBX2, PBX3, PBX4, PBXIP1, PC, PCBD1,PCBD2, PCBP1, PCBP2, PCBP3, PCBP4, PCCA, PCCB, PCDH1, PCDH10, PCDH11X,PCDH11Y, PCDH12, PCDH15, PCDH17, PCDH18, PCDH19, PCDH20, PCDH7, PCDH8,PCDH9, PCDHA1, PCDHA10, PCDHA11, PCDHA12, PCDHA13, PCDHA2, PCDHA3,PCDHA4, PCDHA5, PCDHA6, PCDHA7, PCDHA8, PCDHA9, PCDHAC1, PCDHAC2,PCDHB1, PCDHB10, PCDHB11, PCDHB12, PCDHB13, PCDHB14, PCDHB15, PCDHB16,PCDHB2, PCDHB3, PCDHB4, PCDHB5, PCDHB6, PCDHB7, PCDHB8, PCDHB9, PCDHGA1,PCDHGA10, PCDHGA11, PCDHGA12, PCDHGA2, PCDHGA3, PCDHGA4, PCDHGA5,PCDHGA6, PCDHGA7, PCDHGA8, PCDHGA9, PCDHGB1, PCDHGB2, PCDHGB3, PCDHGB4,PCDHGB5, PCDHGB6, PCDHGB7, PCDHGC3, PCDHGC4, PCDHGC5, PCED1A, PCED1B,PCF11, PCGF1, PCGF2, PCGF3, PCGF5, PCGF6, PCID2, PCIF1, PCK1, PCK2,PCLAF, PCLO, PCM1, PCMT1, PCMTD1, PCMTD2, PCNA, PCNP, PCNT, PCNX1,PCNX2, PCNX3, PCNX4, PCOLCE, PCOLCE2, PCOTH, PCP2, PCP4, PCP4L1, PCSK1,PCSK1N, PCSK2, PCSK4, PCSK5, PCSK6, PCSK7, PCSK9, PCTP, PCYOX1, PCYOX1L,PCYT1A, PCYT1B, PCYT2, PDAP1, PDC, PDCD1, PDCD10, PDCD11, PDCD1LG2,PDCD2, PDCD2L, PDCD4, PDCD5, PDCD6, PDCD6IP, PDCD7, PDCL, PDCL2, PDCL3,PDE10A, PDE11A, PDE12, PDE1A, PDE1B, PDE1C, PDE2A, PDE3A, PDE3B, PDE4A,PDE4B, PDE4C, PDE4D, PDE4DIP, PDE5A, PDE6A, PDE6B, PDE6C, PDE6D, PDE6G,PDE6H, PDE7A, PDE7B, PDE8A, PDE8B, PDE9A, PDF, PDGFA, PDGFB, PDGFC,PDGFD, PDGFRA, PDGFRB, PDGFRL, PDHA1, PDHA2, PDHB, PDHX, PDIA2, PDIA3,PDIA4, PDIA5, PDIA6, PDIK1L, PDILT, PDK1, PDK2, PDK3, PDK4, PDLIM1,PDLIM2, PDLIM3, PDLIM4, PDLIM5, PDLIM7, PDP1, PDP2, PDPK1, PDPN, PDPR,PDRG1, PDS5A, PDS5B, PDSS1, PDSS2, PDX1, PDXDC1, PDXK, PDXP, PDYN,PDZD11, PDZD2, PDZD3, PDZD4, PDZD7, PDZD8, PDZD9, PDZK1, PDZK1IP1,PDZRN3, PDZRN4, PEA15, PEAK1, PEAR1, PEBP1, PEBP4, PECAM1, PECR, PEF1,PEG10, PEG3, PELI1, PELI2, PELI3, PELO, PELP1, PEMT, PENK, PEPD, PER1,PER2, PER3, PERM1, PERP, PES1, PET100, PET117, PEX1, PEX10, PEX11A,PEX11B, PEX11G, PEX12, PEX13, PEX14, PEX16, PEX19, PEX2, PEX26, PEX3,PEX5, PEX5L, PEX6, PEX7, PF4, PF4V1, PFAS, PFDN1, PFDN2, PFDN4, PFDN5,PFDN6, PFKFB1, PFKFB2, PFKFB3, PFKFB4, PFKL, PFKM, PFKP, PFN1, PFN2,PFN3, PFN4, PGA3, PGA4, PGA5, PGAM1, PGAM2, PGAM4, PGAM5, PGAP1, PGAP2,PGAP3, PGBD1, PGBD2, PGBD4, PGBD5, PGC, PGD, PGF, PGGHG, PGGT1B, PGK1,PGK2, PGLS, PGLYRP1, PGLYRP2, PGLYRP3, PGLYRP4, PGM1, PGM2, PGM2L1,PGM3, PGM5, PGP, PGPEP1, PGPEP1L, PGR, PGRMC1, PGRMC2, PGS1, PHACTR1,PHACTR2, PHACTR3, PHACTR4, PHAX, PHB, PHB2, PHC1, PHC2, PHC3, PHEX,PHF1, PHF10, PHF11, PHF12, PHF13, PHF14, PHF19, PHF2, PHF20, PHF20L1,PHF21A, PHF21B, PHF23, PHF24, PHF3, PHF5A, PHF6, PHF7, PHF8, PHGDH,PHGR1, PHIP, PHKA1, PHKA2, PHKB, PHKG1, PHKG2, PHLDA1, PHLDA2, PHLDA3,PHLDB1, PHLDB2, PHLDB3, PHLPP1, PHLPP2, PHOSPHO1, PHOSPHO2, PHOX2A,PHOX2B, PHPT1, PHRF1, PHTF1, PHTF2, PHYH, PHYHD1, PHYHIP, PHYHIPL,PHYKPL, PI15, PI16, PI3, PI4K2A, PI4K2B, PI4KA, PI4 KB, PIANP, PIAS 1,PIAS2, PIAS3, PIAS4, PIBF 1, PICALM, PICK 1, PID 1, PIDD 1, PIEZO 1,PIEZO2, PIF 1, PIFO, PIGA, PIGB, PIGBOS 1, PIGC, PIGF, PIGG, PIGH, PIGK,PIGL, PIGM, PIGN, PIGO, PIGP, PIGQ, PIGR, PIGS, PIGT, PIGU, PIGV, PIGW,PIGX, PIGY, PIGZ, PIH1D1, PIH1D2, PIH1D3, PIK3AP1, PIK3C2A, PIK3C2B,PIK3C2G, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1,PIK3R2, PIK3R3, PIK3R4, PIK3R5, PIK3R6, PIKFYVE, PILRA, PILRB, PIM1,PIM2, PIM3, PIMREG, PINE PIN4, PINK1, PINLYP, PINX1, PIP, PIP4K2A,PIP4K2B, PIP4K2C, PIP5K1A, PIP5K1B, PIP5K1C, PIP5KLE PIPDX, PIR, PIRT,PISD, PITHD1, PITPNA, PITPNB, PITPNC1, PITPNM1, PITPNM2, PITPNM3,PITRM1, PITX1, PITX2, PITX3, PIWILE PIWIL2, PIWIL3, PIWIL4, PJA1, PJA2,PKD1, PKD 1L 1, PKD 1L2, PKD 1 L3, PKD2, PKD2L 1, PKD2L2, PKDCC, PKDREJ,PKHD 1, PKHD1L1, PKIA, PKIB, PKIG, PKLR, PKM, PKMYT1, PKN1, PKN2, PKN3,PKNOX1, PKNOX2, PKP1, PKP2, PKP3, PKP4, PLA1A, PLA2G10, PLA2G12A,PLA2G12B, PLA2G15, PLA2G16, PLA2G1B, PLA2G2A, PLA2G2C, PLA2G2D, PLA2G2E,PLA2G2F, PLA2G3, PLA2G4A, PLA2G4B, PLA2G4C, PLA2G4D, PLA2G4E, PLA2G4F,PLA2G5, PLA2G6, PLA2G7, PLA2R1, PLAA, PLAC1, PLAC4, PLAC8, PLAC8L1,PLAC9, PLAG1, PLAGL1, PLAGL2, PLAT, PLAU, PLAUR, PLB1, PLBD1, PLBD2,PLCB1, PLCB2, PLCB3, PLCB4, PLCD1, PLCD3, PLCD4, PLCE1, PLCG1, PLCG2,PLCH1, PLCH2, PLCL1, PLCL2, PLCXD1, PLCXD2, PLCXD3, PLCZ1, PLD1, PLD2,PLD3, PLD4, PLD5, PLD6, PLEC, PLEK, PLEK2, PLEKHA1, PLEKHA2, PLEKHA3,PLEKHA4, PLEKHA5, PLEKHA6, PLEKHA7, PLEKHA8, PLEKHB1, PLEKHB2, PLEKHD1,PLEKHF1, PLEKHF2, PLEKHG1, PLEKHG2, PLEKHG3, PLEKHG4, PLEKHG4B, PLEKHG5,PLEKHG6, PLEKHG7, PLEKHH1, PLEKHH2, PLEKHH3, PLEKHJ1, PLEKHM1, PLEKHM2,PLEKHM3, PLEKHN1, PLEKHO1, PLEKHG2, PLEKHS1, PLET1, PLG, PLGLB1, PLGLB2,PLGRKT, PLIN1, PLIN2, PLIN3, PLIN4, PLIN5, PLK1, PLK2, PLK3, PLK4, PLK5,PLLP, PLN, PLOD1, PLOD2, PLOD3, PLP1, PLP2, PLPBP, PLPP1, PLPP2, PLPP3,PLPP4, PLPP5, PLPP6, PLPP7, PLPPR1, PLPPR2, PLPPR3, PLPPR4, PLPPRS,PLRG1, PLS 1, PLS3, PLSCR1, PLSCR2, PLSCR3, PLSCR4, PLSCR5, PLTP, PLVAP,PLXDC1, PLXDC2, PLXNA1, PLXNA2, PLXNA3, PLXNA4, PLXNB1, PLXNB2, PLXNB3,PLXNC1, PLXND1, PM20D1, PM20D2, PMAIP1, PMCH, PMEL, PMEPA1, PMF1,PMF1-BGLAP, PMFBP1, PML, PMM1, PMM2, PMP2, PMP22, PMPCA, PMPCB, PMS1,PMS2, PMVK, PNCK, PNISR, PNKD, PNKP, PNLDC1, PNLIP, PNLIPRP1, PNLIPRP2,PNLIPRP3, PNMA1, PNMA2, PNMA3, PNMA5, PNMA6A, PNMA6E, PNMA6F, PNMA8A,PNMA8B, PNMA8C, PNMT, PNN, PNO1, PNOC, PNP, PNPLA1, PNPLA2, PNPLA3,PNPLA4, PNPLA5, PNPLA6, PNPLA7, PNPLA8, PNPO, PNPT1, PNRC1, PNRC2,POC1A, POC1B, POC1B-GALNT4, POC5, PODN, PODNL1, PODXL, PODXL2, POF1B,POFUT1, POFUT2, POGK, POGLUT1, POGZ, POLA1, POLA2, POLB, POLD1, POLD2,POLD3, POLD4, POLDIP2, POLDIP3, POLE, POLE2, POLE3, POLE4, POLG, POLG2,POLH, POLI, POLK, POLL, POLM, POLN, POLQ, POLR1A, POLR1B, POLR1C,POLR1D, POLR1E, POLR2A, POLR2B, POLR2C, POLR2D, POLR2E, POLR2F, POLR2G,POLR2H, POLR2I, POLR2J, POLR2J2, POLR2J3, POLR2K, POLR2L, POLR2M,POLR3A, POLR3B, POLR3C, POLR3D, POLR3E, POLR3F, POLR3G, POLR3GL, POLR3H,POLR3K, POLRMT, POM121, POM121C, POM121L12, POM121L2, POMC, POMGNT1,POMGNT2, POMK, POMP, POMT1, POMT2, POMZP3, PON1, PON2, PON3, POP1, POP4,POPS, POP7, POPDC2, POPDC3, POR, PORCN, POSTN, POT1, POTEA, POTEB,POTEB2, POTEB3, POTEC, POTED, POTEE, POTEF, POTEG, POTEH, POTEI, POTEJ,POTEM, POU1F1, POU2AF1, POU2F1, POU2F2, POU2F3, POU3F1, POU3F2, POU3F3,POU3F4, POU4F1, POU4F2, POU4F3, POU5F1, POU5F1B, POU5F2, POU6F1, POU6F2,PP2D1, PPA1, PPA2, PPAN, PPAN-P2RY11, PPARA, PPARD, PPARG, PPARGC1A,PPARGC1B, PPAT, PPBP, PPCDC, PPCS, PPDPF, PPEF1, PPEF2, PPFIA1, PPFIA2,PPFIA3, PPFIA4, PPFIBP1, PPFIBP2, PPHLN1, PPIA, PPIAL4A, PPIAL4C,PPIAL4D, PPIAL4E, PPIAL4F, PPIAL4G, PPIB, PPIC, PPID, PPIE, PPIF, PPIG,PPIH, PPIL1, PPIL2, PPIL3, PPIL4, PPIL6, PPIP5K1, PPIP5K2, PPL, PPM1A,PPM1B, PPM1D, PPM1E, PPM1F, PPM1G, PPM1H, PPM1J, PPM1K, PPM1L, PPM1M,PPM1N, PPME1, PPDX, PPP1CA, PPP1CB, PPP1CC, PPP1R10, PPP1R11, PPP1R12A,PPP1R12B, PPP1R12C, PPP1R13B, PPP1R13L, PPP1R14A, PPP1R14B, PPP1R14C,PPP1R14D, PPP1R15A, PPP1R15B, PPP1R16A, PPP1R16B, PPP1R17, PPP1R18,PPP1R1A, PPP1R1B, PPP1R1C, PPP1R2, PPP1R21, PPP1R26, PPP1R27, PPP1R2P3,PPP1R2P9, PPP1R32, PPP1R35, PPP1R36, PPP1R37, PPP1R3A, PPP1R3B, PPP1R3C,PPP1R3D, PPP1R3E, PPP1R3F, PPP1R3G, PPP1R42, PPP1R7, PPP1R8, PPP1R9A,PPP1R9B, PPP2CA, PPP2CB, PPP2R1A, PPP2R1B, PPP2R2A, PPP2R2B, PPP2R2C,PPP2R2D, PPP2R3A, PPP2R3B, PPP2R3C, PPP2R5A, PPP2R5B, PPP2R5C, PPP2R5D,PPP2R5E, PPP3CA, PPP3CB, PPP3CC, PPP3R1, PPP3R2, PPP4C, PPP4R1, PPP4R2,PPP4R3A, PPP4R3B, PPP4R3CP, PPP4R4, PPP5C, PPP5D1, PPP6C, PPP6R1,PPP6R2, PPP6R3, PPRC1, PPT1, PPT2, PPT2-EGFL8, PPTC7, PPWD1, PPY, PQBP1,PQLC1, PQLC2, PQLC2L, PQLC3, PRAC1, PRAC2, PRADC1, PRAF2, PRAG1, PRAM1,PRAME, PRAMEF1, PRAMEF10, PRAMEF11, PRAMEF12, PRAMEF13, PRAMEF14,PRAMEF15, PRAMEF17, PRAMEF18, PRAMEF19, PRAMEF2, PRAMEF20, PRAMEF25,PRAMEF26, PRAMEF27, PRAMEF33, PRAMEF4, PRAMEF5, PRAMEF6, PRAMEF7,PRAMEF8, PRAMEF9, PRAP1, PRB1, PRB2, PRB3, PRB4, PRC1, PRCC, PRCD, PRCP,PRDM1, PRDM10, PRDM11, PRDM12, PRDM13, PRDM14, PRDM15, PRDM16, PRDM2,PRDM4, PRDM5, PRDM6, PRDM7, PRDM8, PRDM9, PRDX1, PRDX2, PRDX3, PRDX4,PRDX5, PRDX6, PREB, PRELID1, PRELID2, PRELID3A, PRELID3B, PRELP, PREP,PREPL, PREX1, PREX2, PRF1, PRG2, PRG3, PRG4, PRH1, PRH2, PRICKLE1,PRICKLE2, PRICKLE3, PRICKLE4, PRIM1, PRIM2, PRIMA1, PRIMPOL, PRKAA1,PRKAA2, PRKAB1, PRKAB2, PRKACA, PRKACB, PRKACG, PRKAG1, PRKAG2, PRKAG3,PRKAR1A, PRKAR1B, PRKAR2A, PRKAR2B, PRKCA, PRKCB, PRKCD, PRKCE, PRKCG,PRKCH, PRKCI, PRKCQ, PRKCSH, PRKCZ, PRKD1, PRKD2, PRKD3, PRKDC, PRKG1,PRKG2, PRKN, PRKRA, PRKRIP1, PRKX, PRL, PRLH, PRLHR, PRLR, PRM1, PRM2,PRM3, PRMT1, PRMT2, PRMT3, PRMT5, PRMT6, PRMT7, PRMT8, PRMT9, PRND,PRNP, PRNT, PROB1, PROC, PROCA1, PROCR, PRODH, PRODH2, PROK1, PROK2,PROKR1, PROKR2, PROM1, PROM2, PROP1, PRORY, PROS1, PROSER1, PROSER2,PROSER3, PROX1, PROX2, PROZ, PRPF18, PRPF19, PRPF3, PRPF31, PRPF38A,PRPF38B, PRPF39, PRPF4, PRPF40A, PRPF40B, PRPF4B, PRPF6, PRPF8, PRPH,PRPH2, PRPS1, PRPS1L1, PRPS2, PRPSAP1, PRPSAP2, PRR11, PRR12, PRR13,PRR14, PRR14L, PRR15, PRR15L, PRR16, PRR18, PRR19, PRR20A, PRR20B,PRR20C, PRR20D, PRR20E, PRR21, PRR22, PRR23A, PRR23B, PRR23C, PRR23D1,PRR23D2, PRR25, PRR26, PRR27, PRR29, PRR3, PRR30, PRR32, PRR34, PRR35,PRR36, PRR4, PRR5, PRR5-ARHGAP8, PRR5L, PRR7, PRR9, PRRC1, PRRC2A,PRRC2B, PRRC2C, PRRG1, PRRG2, PRRG3, PRRG4, PRRT1, PRRT2, PRRT3, PRRT4,PRRX1, PRRX2, PRSS1, PRSS12, PRSS16, PRSS2, PRSS21, PRSS22, PRSS23,PRSS27, PRSS3, PRSS33, PRSS35, PRSS36, PRSS37, PRSS38, PRSS41, PRSS42,PRSS45, PRSS46, PRSS48, PRSS50, PRSS51, PRSS53, PRSS54, PRSS55, PRSS56,PRSS57, PRSS58, PRSS8, PRTFDC1, PRTG, PRTN3, PRUNE1, PRUNE2, PRX, PRY,PRY2, PSAP, PSAPL1, PSAT1, PSCA, PSD, PSD2, PSD3, PSD4, PSEN1, PSEN2,PSENEN, PSG1, PSG11, PSG2, PSG3, PSG4, PSG5, PSG6, PSG7, PSG8, PSG9,PSIP1, PSKH1, PSKH2, PSMA1, PSMA2, PSMA3, PSMA4, PSMA5, PSMA6, PSMA7,PSMA8, PSMB1, PSMB10, PSMB11, PSMB2, PSMB3, PSMB4, PSMB5, PSMB6, PSMB7,PSMB8, PSMB9, PSMC1, PSMC2, PSMC3, PSMC3IP, PSMC4, PSMC5, PSMC6, PSMD1,PSMD10, PSMD11, PSMD12, PSMD13, PSMD14, PSMD2, PSMD3, PSMD4, PSMD5,PSMD6, PSMD7, PSMD8, PSMD9, PSME1, PSME2, PSME3, PSME4, PSMF1, PSMG1,PSMG2, PSMG3, PSMG4, PSORS1C1, PSORS1C2, PSPC1, PSPH, PSPN, PSRC1, PSTK,PSTPIP1, PSTPIP2, PTAFR, PTAR1, PTBP1, PTBP2, PTBP3, PTCD1, PTCD2,PTCD3, PTCH1, PTCH2, PTCHD1, PTCHD3, PTCHD4, PTCRA, PTDSS1, PTDSS2,PTEN, PTER, PTF1A, PTGDR, PTGDR2, PTGDS, PTGER1, PTGER2, PTGER3, PTGER4,PTGES, PTGES2, PTGES3, PTGES3L, PTGES3L-AARSD1, PTGFR, PTGFRN, PTGIR,PTGIS, PTGR1, PTGR2, PTGS1, PTGS2, PTH, PTH1R, PTH2, PTH2R, PTHLH, PTK2,PTK2B, PTK6, PTK7, PTMA, PTMS, PTN, PTOV1, PTP4A1, PTP4A2, PTP4A3, PTPA,PTPDC1, PTPMT1, PTPN1, PTPN11, PTPN12, PTPN13, PTPN14, PTPN18, PTPN2,PTPN20, PTPN21, PTPN22, PTPN23, PTPN3, PTPN4, PTPN5, PTPN6, PTPN7,PTPN9, PTPRA, PTPRB, PTPRC, PTPRCAP, PTPRD, PTPRE, PTPRF, PTPRG, PTPRH,PTPRJ, PTPRK, PTPRM, PTPRN, PTPRN2, PTPRO, PTPRQ, PTPRR, PTPRS, PTPRT,PTPRU, PTPRZ1, PTRH1, PTRH2, PTRHD1, PTS, PTTG1, PTTG1IP, PTTG2, PTX3,PTX4, PUDP, PUF60, PUM1, PUM2, PUM3, PURA, PURB, PURG, PUS1, PUS10,PUS3, PUS7, PUS7L, PUSL1, PVALB, PVR, PVRIG, PWP1, PWP2, PWWP2A, PWWP2B,PXDC1, PXDN, PXDNL, PXK, PXMP2, PXMP4, PXN, PXT1, PXYLP1, PYCARD, PYCR1,PYCR2, PYCR3, PYDC1, PYDC2, PYGB, PYGL, PYGM, PYGO1, PYGO2, PYHIN1,PYM1, PYROXD1, PYROXD2, PYURF, PYY, PZP, QARS, QDPR, QKI, QPCT, QPCTL,QPRT, QRFP, QRFPR, QRICHL QRICH2, QRSL1, QSER1, QSOX1, QSOX2, QTRT1,QTRT2, R3HCC1, R3HCC1L, R3HDM1, R3HDM2, R3HDM4, R3HDML, RAB10, RAB11A,RAB11B, RAB11FIP1, RAB11FIP2, RAB11FIP3, RAB11FIP4, RAB11FIP5, RAB12,RAB13, RAB14, RAB15, RAB17, RAB18, RAB19, RAB1A, RAB1B, RAB20, RAB21,RAB22A, RAB23, RAB24, RAB25, RAB26, RAB27A, RAB27B, RAB28, RAB29, RAB2A,RAB2B, RAB30, RAB31, RAB32, RAB33A, RAB33B, RAB34, RAB35, RAB36, RAB37,RAB38, RAB39A, RAB39B, RAB3A, RAB3B, RAB3C, RAB3D, RAB3GAP1, RAB3GAP2,RAB3IL1, RAB3IP, RAB40A, RAB40AL, RAB40B, RAB40C, RAB41, RAB42, RAB43,RAB44, RAB4A, RAB4B, RAB4B-EGLN2, RAB5A, RAB5B, RAB5C, RAB6A, RAB6B,RAB6C, RAB7A, RAB7B, RAB8A, RAB8B, RAB9A, RAB9B, RABAC1, RABEP1, RABEP2,RABEPK, RABGAP1, RABGAP1L, RABGEF1, RABGGTA, RABGGTB, RABIF, RABL2A,RABL2B, RABL3, RABL6, RAC1, RAC2, RAC3, RACGAP1, RACK1, RAD1, RAD17,RAD18, RAD21, RAD21L1, RAD23A, RAD23B, RAD50, RAD51, RAD51AP1, RAD51AP2,RAD51B, RAD51C, RAD51D, RAD52, RAD54B, RAD54L, RAD54L2, RAD9A, RAD9B,RADIL, RAE1, RAET1E, RAET1G, RAET1L, RAF1, RAG1, RAG2, RAI1, RAI14,RAI2, RALA, RALB, RALBP1, RALGAPA1, RALGAPA2, RALGAPB, RALGDS, RALGPS1,RALGPS2, RALY, RALYL, RAMP1, RAMP2, RAMP3, RAN, RANBP1, RANBP10,RANBP17, RANBP2, RANBP3, RANBP3L, RANBP6, RANBP9, RANGAP1, RANGRF,RAP1A, RAP1B, RAP1GAP, RAP1GAP2, RAP1GDS1, RAP2A, RAP2B, RAP2C, RAPGEF1,RAPGEF2, RAPGEF3, RAPGEF4, RAPGEF5, RAPGEF6, RAPGEFL1, RAPH1, RAPSN,RARA, RARB, RARG, RARRES1, RARRES2, RARRES3, RARS, RARS2, RASA1, RASA2,RASA3, RASA4, RASA4B, RASAL1, RASAL2, RASAL3, RASD1, RASD2, RASEF,RASGEF1A, RASGEF1B, RASGEF1C, RASGRF1, RASGRF2, RASGRP1, RASGRP2,RASGRP3, RASGRP4, RASIP1, RASL10A, RASL10B, RASL11A, RASL11B, RASL12,RASSF1, RASSF10, RASSF2, RASSF3, RASSF4, RASSF5, RASSF6, RASSF7, RASSF8,RASSF9, RAVER1, RAVER2, RAX, RAX2, RB1, RB1CC1, RBAK, RBAK-RBAKDN,RBBP4, RBBP5, RBBP6, RBBP7, RBBP8, RBBP8NL, RBBP9, RBCK1, RBFA, RBFOX1,RBFOX2, RBFOX3, RBKS, RBL1, RBL2, RBM10, RBM11, RBM12, RBM12B, RBM14,RBM14-RBM4, RBM15, RBM15B, RBM17, RBM18, RBM19, RBM20, RBM22, RBM23,RBM24, RBM25, RBM26, RBM27, RBM28, RBM3, RBM33, RBM34, RBM38, RBM39,RBM4, RBM41, RBM42, RBM43, RBM44, RBM45, RBM46, RBM47, RBM48, RBM4B,RBM5, RBM6, RBM7, RBM8A, RBMS1, RBMS2, RBMS3, RBMX, RBMX2, RBMXL1,RBMXL2, RBMXL3, RBMY1A1, RBMY1B, RBMY1D, RBMY1E, RBMY1F, RBMY1J, RBP1,RBP2, RBP3, RBP4, RBP5, RBP7, RBPJ, RBPJL, RBPMS, RBPMS2, RBSN, RBX1,RC3H1, RC3H2, RCAN1, RCAN2, RCAN3, RCBTB1, RCBTB2, RCC1, RCC1L, RCC2,RCCD1, RCE1, RCHY1, RCL1, RCN1, RCN2, RCN3, RCOR1, RCOR2, RCOR3, RCSD1,RCVRN, RD3, RD3L, RDH10, RDH11, RDH12, RDH13, RDH14, RDH16, RDH5, RDH8,RDM1, RDX, REC114, REC8, RECK, RECQL, RECQL4, RECQL5, REEP1, REEP2,REEP3, REEP4, REEP5, REEP6, REG1A, REG1B, REG3A, REG3G, REG4, REL, RELA,RELB, RELL1, RELL2, RELN, RELT, REM1, REM2, REN, RENBP, REP15, REPIN1,REPS1, REPS2, RER1, RERE, RERG, RERGL, RESP18, REST, RET, RETN, RETNLB,RETREG1, RETREG2, RETREG3, RETSAT, REV1, REV3L, REXO1, REXO2, REXO4,REXO5, RFC1, RFC2, RFC3, RFC4, RFC5, RFESD, RFFL, RFK, RFLNA, RFLNB,RFNG, RFPL1, RFPL2, RFPL3, RFPL3S, RFPL4A, RFPL4AL1, RFPL4B, RFT1,RFTN1, RFTN2, RFWD2, RFWD3, RFX1, RFX2, RFX3, RFX4, RFX5, RFX6, RFX7,RFX8, RFXANK, RFXAP, RGCC, RGL1, RGL2, RGL3, RGL4, RGMA, RGMB, RGN,RGP1, RGPD1, RGPD2, RGPD3, RGPD4, RGPD5, RGPD6, RGPD8, RGR, RGS1, RGS10,RGS11, RGS12, RGS13, RGS14, RGS16, RGS17, RGS18, RGS19, RGS2, RGS20,RGS21, RGS22, RGS3, RGS4, RGS5, RGS6, RGS7, RGS7BP, RGS8, RGS9, RGS9BP,RGSL1, RHAG, RHBDD1, RHBDD2, RHBDD3, RHBDF1, RHBDF2, RHBDL1, RHBDL2,RHBDL3, RHBG, RHCE, RHCG, RHD, RHEB, RHEBL1, RHNO1, RHO, RHOA, RHOB,RHOBTB1, RHOBTB2, RHOBTB3, RHOC, RHOD, RHOF, RHOG, RHOH, RHOJ, RHOQ,RHOT1, RHOT2, RHOU, RHOV, RHOXF1, RHOXF2, RHOXF2B, RHPN1, RHPN2, RIBC1,RIBC2, RIC1, RIC3, RIC8A, RIC8B, RICTOR, RIDA, RIF1, RIIAD1, RILP,RILPL1, RILPL2, RIMBP2, RIMBP3, RIMBP3B, RIMBP3C, RIMKLA, RIMKLB, RIMS1,RIMS2, RIMS3, RIMS4, RIN1, RIN2, RIN3, RING1, RINL, RINT1, RIOK1, RIOK2,RIOK3, RIOX1, RIOX2, RIPK1, RIPK2, RIPK3, RIPK4, RIPOR1, RIPOR2, RIPOR3,RIPPLY1, RIPPLY2, RIPPLY3, RIT1, RIT2, RITA1, RLBP1, RLF, RLIM, RLN1,RLN2, RLN3, RMDN1, RMDN2, RMDN3, RMI1, RMI2, RMND1, RMND5A, RMND5B,RNASE1, RNASE10, RNASE11, RNASE12, RNASE13, RNASE2, RNASE3, RNASE4,RNASE6, RNASE7, RNASE8, RNASE9, RNASEH1, RNASEH2A, RNASEH2B, RNASEH2C,RNASEK, RNASEK-C17orf49, RNASEL, RNASET2, RND1, RND2, RND3, RNF 10, RNF103, RNF103-CHMP3, RNF11, RNF111, RNF112, RNF113A, RNF113B, RNF114,RNF115, RNF121, RNF122, RNF123, RNF125, RNF126, RNF128, RNF13, RNF130,RNF133, RNF135, RNF138, RNF139, RNF14, RNF141, RNF144A, RNF144B, RNF145,RNF146, RNF148, RNF149, RNF150, RNF151, RNF152, RNF157, RNF165, RNF166,RNF167, RNF168, RNF169, RNF17, RNF170, RNF175, RNF180, RNF181, RNF182,RNF183, RNF185, RNF186, RNF187, RNF19A, RNF19B, RNF2, RNF20, RNF207,RNF208, RNF212, RNF212B, RNF213, RNF214, RNF215, RNF216, RNF217, RNF219,RNF220, RNF222, RNF223, RNF224, RNF225, RNF24, RNF25, RNF26, RNF31,RNF32, RNF34, RNF38, RNF39, RNF4, RNF40, RNF41, RNF43, RNF44, RNF5,RNF6, RNF7, RNF8, RNFT1, RNFT2, RNGTT, RNH1, RNLS, RNMT, RNPC3, RNPEP,RNPEPL1, RNPS1, ROBO1, ROBO2, ROBO3, ROBO4, ROCK1, ROCK2, ROGDI, ROM1,ROMO1, ROPN1, ROPN1B, ROPN1L, ROR1, ROR2, RORA, RORB, RORC, ROS1, RP1,RP1L1, RP2, RP9, RPA1, RPA2, RPA3, RPA4, RPAIN, RPAP1, RPAP2, RPAP3,RPE, RPE65, RPEL1, RPF1, RPF2, RPGR, RPGRIP1, RPGRIP1L, RPH3A, RPH3AL,RPIA, RPL10, RPL10A, RPL10L, RPL11, RPL12, RPL13, RPL13A, RPL14, RPL15,RPL17, RPL17-C18orf32, RPL18, RPL18A, RPL19, RPL21, RPL22, RPL22L1,RPL23, RPL23A, RPL24, RPL26, RPL26L1, RPL27, RPL27A, RPL28, RPL29, RPL3,RPL30, RPL31, RPL32, RPL34, RPL35, RPL35A, RPL36, RPL36A,RPL36A-HNRNPH2, RPL36AL, RPL37, RPL37A, RPL38, RPL39, RPL39L, RPL3L,RPL4, RPL41, RPL5, RPL6, RPL7, RPL7A, RPL7L1, RPL8, RPL9, RPLP0, RPLP1,RPLP2, RPN1, RPN2, RPP14, RPP21, RPP25, RPP25L, RPP30, RPP38, RPP40,RPRD1A, RPRD1B, RPRD2, RPRM, RPRML, RPS10, RPS10-NUDT3, RPS11, RPS12,RPS13, RPS14, RPS15, RPS15A, RPS16, RPS17, RPS18, RPS19, RPS19BP1, RPS2,RPS20, RPS21, RPS23, RPS24, RPS25, RPS26, RPS27, RPS27A, RPS27L, RPS28,RPS29, RPS3, RPS3A, RPS4X, RPS4Y1, RPS4Y2, RPS5, RPS6, RPS6KA1, RPS6KA2,RPS6KA3, RPS6KA4, RPS6KA5, RPS6KA6, RPS6KB1, RPS6KB2, RPS6KC1, RPS6KL1,RPS7, RPS8, RPS9, RPSA, RPTN, RPTOR, RPUSD1, RPUSD2, RPUSD3, RPUSD4,RRAD, RRAGA, RRAGB, RRAGC, RRAGD, RRAS, RRAS2, RRBP1, RREB1, RRH, RRM1,RRM2, RRM2B, RRN3, RRNAD1, RRP1, RRP12, RRP15, RRP1B, RRP36, RRP7A,RRP8, RRP9, RRS1, RS1, RSAD1, RSAD2, RSBN1, RSBN1L, RSC1A1, RSF1, RSG1,RSL1D1, RSL24D1, RSPH1, RSPH10B, RSPH10B2, RSPH14, RSPH3, RSPH4A,RSPH6A, RSPH9, RSPO1, RSPO2, RSPO3, RSPO4, RSPRY1, RSRC1, RSRC2, RSRP1,RSU1, RTBDN, RTCA, RTCB, RTEL1, RTEL1-TNFRSF6B, RTF1, RTFDC1, RTKN,RTKN2, RTL1, RTL10, RTL3, RTL4, RTL5, RTL6, RTL8A, RTL8B, RTL8C, RTL9,RTN1, RTN2, RTN3, RTN4, RTN4IP1, RTN4R, RTN4RL1, RTN4RL2, RTP1, RTP2,RTP3, RTP4, RTP5, RTTN, RUBCN, RUBCNL, RUFY1, RUFY2, RUFY3, RUFY4,RUNDC1, RUNDC3A, RUNDC3B, RUNX1, RUNX1T1, RUNX2, RUNX3, RUSC1, RUSC2,RUVBL1, RUVBL2, RWDD1, RWDD2A, RWDD2B, RWDD3, RWDD4, RXFP1, RXFP2,RXFP3, RXFP4, RXRA, RXRB, RXRG, RYBP, RYK, RYR1, RYR2, RYR3, S100A1,S100A10, S100A11, S100A12, S100A13, S100A14, S100A16, S100A2, S100A3,S100A4, S100A5, S100A6, S100A7, S100A7A, S100A7L2, S100A8, S100A9,S100B, S100G, S100P, S100PBP, S100Z, S1PR1, S1PR2, S1PR3, S1PR4, S1PR5,SAA1, SAA2, SAA2-SAA4, SAA4, SAAL1, SAC3D1, SACM1L, SACS, SAE1, SAFB,SAFB2, SAG, SAGE1, SALL1, SALL2, SALL3, SALL4, SAMD1, SAMD10, SAMD11,SAMD12, SAMD13, SAMD14, SAMD15, SAMD3, SAMD4A, SAMD4B, SAMD5, SAMD7,SAMD8, SAMD9, SAMD9L, SAM1D1, SAMM50, SAMSN1, SAP130, SAP18, SAP25,SAP30, SAP3OBP, SAP30L, SAPCD1, SAPCD2, SAR1A, SAR1B, SARAF, SARDH,SARM1, SARNP, SARS, SARS2, SART1, SART3, SASH1, SASH3, SASS6, SAT1,SAT2, SATB1, SATB2, SATL1, SAV1, SAXO1, SAXO2, SAYSD1, SBDS, SBF1, SBF2,SBK1, SBK2, SBK3, SBNO1, SBNO2, SBSN, SBSPON, SC5D, SCAF1, SCAF11,SCAF4, SCAF8, SCAI, SCAMPI, SCAMP2, SCAMP3, SCAMP4, SCAMP5, SCAND1,SCAP, SCAPER, SCARA3, SCARA5, SCARB1, SCARB2, SCARF1, SCARF2, SCART1,SCCPDH, SCD, SCD5, SCEL, SCFD1, SCFD2, SCG2, SCG3, SCG5, SCGB1A1,SCGB1C1, SCGB1C2, SCGB1D1, SCGB1D2, SCGB1D4, SCGB2A1, SCGB2A2, SCGB2B2,SCGB3A1, SCGB3A2, SCGN, SCHIP1, SCIMP, SCIN, SCLT1, SCLY, SCMH1, SCML1,SCML2, SCML4, SCN10A, SCN11A, SCN1A, SCN1B, SCN2A, SCN2B, SCN3A, SCN3B,SCN4A, SCN4B, SCN5A, SCN7A, SCN8A, SCN9A, SCNM1, SCNN1A, SCNN1B, SCNN1D,SCNN1G, SCO1, SCO2, SCOC, SCP2, SCP2D1, SCPEP1, SCRG1, SCRIB, SCRN1,SCRN2, SCRN3, SCRT1, SCRT2, SCT, SCTR, SCUBE1, SCUBE2, SCUBE3, SCX,SCYL1, SCYL2, SCYL3, SDAD1, SDC1, SDC2, SDC3, SDC4, SDCBP, SDCBP2,SDCCAG3, SDCCAG8, SDE2, SDF2, SDF2L1, SDF4, SDHA, SDHAF1, SDHAF2,SDHAF3, SDHAF4, SDHB, SDHC, SDHD, SDK1, SDK2, SDR16C5, SDR39U1, SDR42E1,SDR42E2, SDR9C7, SDS, SDSL, SEBOX, SEC11A, SEC11C, SEC13, SEC14L1,SEC14L2, SEC14L3, SEC14L4, SEC14L5, SEC14L6, SEC16A, SEC16B, SEC22A,SEC22B, SEC22C, SEC23A, SEC23B, SEC23IP, SEC24A, SEC24B, SEC24C, SEC24D,SEC31A, SEC31B, SEC61A1, SEC61A2, SEC61B, SEC61G, SEC62, SEC63,SECISBP2, SECISBP2L, SECTM1, SEH1L, SEL1L, SEL1L2, SEL1L3, SELE,SELENBP1, SELENOF, SELENOH, SELENOI, SELENOK, SELENOM, SELENON, SELENOO,SELENOP, SELENOS, SELENOT, SELENOV, SELENOW, SELL, SELP, SELPLG, SEMI,SEMA3A, SEMA3B, SEMA3C, SEMA3D, SEMA3E, SEMA3F, SEMA3G, SEMA4A, SEMA4B,SEMA4C, SEMA4D, SEMA4F, SEMA4G, SEMA5A, SEMA5B, SEMA6A, SEMA6B, SEMA6C,SEMA6D, SEMA7A, SEMG1, SEMG2, SENP1, SENP2, SENP3, SENP3-EIF4A1, SENP5,SENP6, SENP7, SENP8, SEPHS1, SEPHS2, SEPSECS, SEPT1, SEPT10, SEPT11,SEPT12, SEPT14, SEPT2, SEPT3, SEPT4, SEPT5, SEPT6, SEPT7, SEPT8, SEPT9,SERAC1, SERBP1, SERF1A, SERF1B, SERF2, SERGEF, SERHL2, SERINC1, SERINC2,SERINC3, SERINC4, SERINC5, SERP1, SERP2, SERPINA1, SERPINA10, SERPINA11,SERPINA12, SERPINA2, SERPINA3, SERPINA4, SERPINA5, SERPINA6, SERPINA7,SERPINA9, SERPINB1, SERPINB10, SERPINB11, SERPINB12, SERPINB13,SERPINB2, SERPINB3, SERPINB4, SERPINB5, SERPINB6, SERPINB7, SERPINB8,SERPINB9, SERPINC1, SERPIND1, SERPINE1, SERPINE2, SERPINE3, SERPINF1,SERPINF2, SERPING1, SERPINH1, SERPINI1, SERPINI2, SERTAD1, SERTAD2,SERTAD3, SERTAD4, SERTM1, SESN1, SESN2, SESN3, SESTD1, SET, SETBP1,SETD1A, SETD1B, SETD2, SETD3, SETD4, SETD5, SETD6, SETD7, SETD9, SETDB1,SETDB2, SETMAR, SETSIP, SETX, SEZ6, SEZ6L, SEZ6L2, SF1, SF3A1, SF3A2,SF3A3, SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6, SFIL SFMBT1, SFMBT2,SFN, SFPQ, SFR1, SFRP1, SFRP2, SFRP4, SFRP5, SFSWAP, SFT2D1, SFT2D2,SFT2D3, SFTA2, SFTA3, SFTPA1, SFTPA2, SFTPB, SFTPC, SFTPD, SFXN1, SFXN2,SFXN3, SFXN4, SFXN5, SGCA, SGCB, SGCD, SGCE, SGCG, SGCZ, SGF29, SGIP1,SGK1, SGK2, SGK3, SGK494, SGMS1, SGMS2, SGO1, SGO2, SGPL1, SGPP1, SGPP2,SGSH, SGSM1, SGSM2, SGSM3, SGTA, SGTB, SH2B1, SH2B2, SH2B3, SH2D1A,SH2D1B, SH2D2A, SH2D3A, SH2D3C, SH2D4A, SH2D4B, SH2D5, SH2D6, SH2D7,SH3BGR, SH3BGRL, SH3BGRL2, SH3BGRL3, SH3BP1, SH3BP2, SH3BP4, SH3BP5,SH3BP5L, SH3D19, SH3D21, SH3GL1, SH3GL2, SH3GL3, SH3GLB1, SH3GLB2,SH3KBP1, SH3PXD2A, SH3PXD2B, SH3RF1, SH3RF2, SH3RF3, SH3TC1, SH3TC2,SH3YL1, SHANK1, SHANK2, SHANK3, SHARPIN, SHB, SHBG, SHC1, SHC2, SHC3,SHC4, SHCBP1, SHCBP1L, SHD, SHE, SHF, SHH, SHISA2, SHISA3, SHISA4,SHISA5, SHISA6, SHISA7, SHISA8, SHISA9, SHKBP1, SHMT1, SHMT2, SHOC2,SHOX, SHOX2, SHPK, SHPRH, SHQ1, SHROOM1, SHROOM2, SHROOM3, SHROOM4,SHTN1, SI, SIAE, SIAH1, SIAH2, SIAH3, SIDT1, SIDT2, SIGIRR, SIGLEC1,SIGLEC10, SIGLEC11, SIGLEC12, SIGLEC14, SIGLEC15, SIGLEC5, SIGLEC6,SIGLEC7, SIGLEC8, SIGLEC9, SIGLECL1, SIGMAR1, SIK1, SIK2, SIK3, SIKE1,SIL1, SIM1, SIM2, SIMC1, SIN3A, SIN3B, SIPA1, SIPA1L1, SIPA1L2, SIPA1L3,SIRPA, SIRPB1, SIRPB2, SIRPD, SIRPG, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5,SIRT6, SIRT7, SIT1, SIVA1, SIX1, SIX2, SIX3, SIX4, SIX5, SIX6, SKA1,SKA2, SKA3, SKAP1, SKAP2, SKI, SKIDA1, SKIL, SKIV2L, SKIV2L2, SKOR1,SKOR2, SKP1, SKP2, SLA, SLA2, SLAIN1, SLAIN2, SLAMF1, SLAMF6, SLAMF7,SLAMF8, SLAMF9, SLBP, SLC10A1, SLC10A2, SLC10A3, SLC10A4, SLC10A5,SLC10A6, SLC10A7, SLC11A1, SLC11A2, SLC12A1, SLC12A2, SLC12A3, SLC12A4,SLC12A5, SLC12A6, SLC12A7, SLC12A8, SLC12A9, SLC13A1, SLC13A2, SLC13A3,SLC13A4, SLC13A5, SLC14A1, SLC14A2, SLC15A1, SLC15A2, SLC15A3, SLC15A4,SLC15A5, SLC16A1, SLC16A10, SLC16A11, SLC16A12, SLC16A13, SLC16A14,SLC16A2, SLC16A3, SLC16A4, SLC16A5, SLC16A6, SLC16A7, SLC16A8, SLC16A9,SLC17A1, SLC17A2, SLC17A3, SLC17A4, SLC17A5, SLC17A6, SLC17A7, SLC17A8,SLC17A9, SLC18A1, SLC18A2, SLC18A3, SLC18B1, SLC19A1, SLC19A2, SLC19A3,SLC1A1, SLC1A2, SLC1A3, SLC1A4, SLC1A5, SLC1A6, SLC1A7, SLC20A1,SLC20A2, SLC22A1, SLC22A10, SLC22A11, SLC22A12, SLC22A13, SLC22A14,SLC22A15, SLC22A16, SLC22A17, SLC22A18, SLC22A18AS, SLC22A2, SLC22A23,SLC22A24, SLC22A25, SLC22A3, SLC22A31, SLC22A4, SLC22A5, SLC22A6,SLC22A7, SLC22A8, SLC22A9, SLC23A1, SLC23A2, SLC23A3, SLC24A1, SLC24A2,SLC24A3, SLC24A4, SLC24A5, SLC25A1, SLC25A10, SLC25A11, SLC25A12,SLC25A13, SLC25A14, SLC25A15, SLC25A16, SLC25A17, SLC25A18, SLC25A19,SLC25A2, SLC25A20, SLC25A21, SLC25A22, SLC25A23, SLC25A24, SLC25A25,SLC25A26, SLC25A27, SLC25A28, SLC25A29, SLC25A3, SLC25A30, SLC25A31,SLC25A32, SLC25A33, SLC25A34, SLC25A35, SLC25A36, SLC25A37, SLC25A38,SLC25A39, SLC25A4, SLC25A40, SLC25A41, SLC25A42, SLC25A43, SLC25A44,SLC25A45, SLC25A46, SLC25A47, SLC25A48, SLC25A5, SLC25A51, SLC25A52,SLC25A53, SLC25A6, SLC26A1, SLC26A10, SLC26A11, SLC26A2, SLC26A3,SLC26A4, SLC26A5, SLC26A6, SLC26A7, SLC26A8, SLC26A9, SLC27A1, SLC27A2,SLC27A3, SLC27A4, SLC27A5, SLC27A6, SLC28A1, SLC28A2, SLC28A3, SLC29A1,SLC29A2, SLC29A3, SLC29A4, SLC2A1, SLC2A10, SLC2A11, SLC2A12, SLC2A13,SLC2A14, SLC2A2, SLC2A3, SLC2A4, SLC2A4RG, SLC2A5, SLC2A6, SLC2A7,SLC2A8, SLC2A9, SLC30A1, SLC30A10, SLC30A2, SLC30A3, SLC30A4, SLC30A5,SLC30A6, SLC30A7, SLC30A8, SLC30A9, SLC31A1, SLC31A2, SLC32A1, SLC33A1,SLC34A1, SLC34A2, SLC34A3, SLC35A1, SLC35A2, SLC35A3, SLC35A4, SLC35A5,SLC35B1, SLC35B2, SLC35B3, SLC35B4, SLC35C1, SLC35C2, SLC35D1, SLC35D2,SLC35D3, SLC35E1, SLC35E2, SLC35E2B, SLC35E3, SLC35E4, SLC35F1, SLC35F2,SLC35F3, SLC35F4, SLC35F5, SLC35F6, SLC35G1, SLC35G2, SLC35G3, SLC35G4,SLC35G5, SLC35G6, SLC36A1, SLC36A2, SLC36A3, SLC36A4, SLC37A1, SLC37A2,SLC37A3, SLC37A4, SLC38A1, SLC38A10, SLC38A11, SLC38A2, SLC38A3,SLC38A4, SLC38A5, SLC38A6, SLC38A7, SLC38A8, SLC38A9, SLC39A1, SLC39A10,SLC39A11, SLC39A12, SLC39A13, SLC39A14, SLC39A2, SLC39A3, SLC39A4,SLC39A5, SLC39A6, SLC39A7, SLC39A8, SLC39A9, SLC3A1, SLC3A2, SLC40A1,SLC41A1, SLC41A2, SLC41A3, SLC43A1, SLC43A2, SLC43A3, SLC44A1, SLC44A2,SLC44A3, SLC44A4, SLC44A5, SLC45A1, SLC45A2, SLC45A3, SLC45A4, SLC46A1,SLC46A2, SLC46A3, SLC47A1, SLC47A2, SLC48A1, SLC4A1, SLC4A10, SLC4A11,SLC4A1AP, SLC4A2, SLC4A3, SLC4A4, SLC4A5, SLC4A7, SLC4A8, SLC4A9,SLC50A1, SLC51A, SLC51B, SLC52A1, SLC52A2, SLC52A3, SLC5A1, SLC5A10,SLC5A11, SLC5A12, SLC5A2, SLC5A3, SLC5A4, SLC5A5, SLC5A6, SLC5A7,SLC5A8, SLC5A9, SLC6A1, SLC6A11, SLC6A12, SLC6A13, SLC6A14, SLC6A15,SLC6A16, SLC6A17, SLC6A18, SLC6A19, SLC6A2, SLC6A20, SLC6A3, SLC6A4,SLC6A5, SLC6A6, SLC6A7, SLC6A8, SLC6A9, SLC7A1, SLC7A10, SLC7A11,SLC7A13, SLC7A14, SLC7A2, SLC7A3, SLC7A4, SLC7A5, SLC7A6, SLC7A6OS,SLC7A7, SLC7A8, SLC7A9, SLC8A1, SLC8A2, SLC8A3, SLC8B1, SLC9A1, SLC9A2,SLC9A3, SLC9A3R1, SLC9A3R2, SLC9A4, SLC9A5, SLC9A6, SLC9A7, SLC9A8,SLC9A9, SLC9B1, SLC9B2, SLC9C1, SLC9C2, SLCO1A2, SLCO1B1, SLCO1B3,SLCO1B7, SLCO1C1, SLCO2A1, SLCO2B1, SLCO3A1, SLCO4A1, SLCO4C1, SLCO5A1,SLCO6A1, SLF1, SLF2, SLFN11, SLFN12, SLFN12L, SLFN13, SLFN14, SLFN5,SLFNL1, SLIRP, SLIT1, SLIT2, SLIT3, SLITRK1, SLITRK2, SLITRK3, SLITRK4,SLITRK5, SLITRK6, SLK, SLMAP, SLN, SLPI, SLTM, SLU7, SLURP1, SLURP2,SLX1A, SLX1B, SLX4, SLX4IP, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6,SMAD7, SMAD9, SMAGP, SMAP1, SMAP2, SMARCA1, SMARCA2, SMARCA4, SMARCA5,SMARCAD1, SMARCAL1, SMARCB1, SMARCC1, SMARCC2, SMARCD1, SMARCD2,SMARCD3, SMARCE1, SMC1A, SMC1B, SMC2, SMC3, SMC4, SMC5, SMC6, SMCHD1,SMCO1, SMCO2, SMCO3, SMCO4, SMCP, SMCR8, SMDT1, SMG1, SMG5, SMG6, SMG7,SMG8, SMG9, SMIM1, SMIM10, SMIM10L1, SMIM10L2A, SMIM10L2B, SMIM11A,SMIM11B, SMIM12, SMIM13, SMIM14, SMIM15, SMIM17, SMIM18, SMIM19, SMIM2,SMIM20, SMIM21, SMIM22, SMIM23, SMIM24, SMIM26, SMIM27, SMIM28, SMIM29,SMIM3, SMIM30, SMIM31, SMIM4, SMIM5, SMIM6, SMIM7, SMIM8, SMIM9, SMKR1,SMLR1, SMN1, SMN2, SMNDC1, SMO, SMOC1, SMOC2, SMOX, SMPD1, SMPD2, SMPD3,SMPD4, SMPDL3A, SMPDL3B, SMPX, SMR3A, SMR3B, SMS, SMTN, SMTNL1, SMTNL2,SMU1, SMUG1, SMURF1, SMURF2, SMYD1, SMYD2, SMYD3, SMYD4, SMYD5, SNAILSNAI2, SNAI3, SNAP23, SNAP25, SNAP29, SNAP47, SNAP91, SNAPC1, SNAPC2,SNAPC3, SNAPC4, SNAPC5, SNAPIN, SNCA, SNCAIP, SNCB, SNCG, SND1, SNED1,SNF 8, SNHG28, SNIP1, SNN, SNPH, SNRK, SNRNP200, SNRNP25, SNRNP27,SNRNP35, SNRNP40, SNRNP48, SNRNP70, SNRPA, SNRPA1, SNRPB, SNRPB2, SNRPC,SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF, SNRPG, SNRPN, SNTA1, SNTB1, SNTB2,SNTG1, SNTG2, SNTN, SNU13, SNUPN, SNURF, SNW1, SNX1, SNX10, SNX11,SNX12, SNX13, SNX14, SNX15, SNX16, SNX17, SNX18, SNX19, SNX2, SNX20,SNX21, SNX22, SNX24, SNX25, SNX27, SNX29, SNX3, SNX30, SNX31, SNX32,SNX33, SNX4, SNX5, SNX6, SNX7, SNX8, SNX9, SOAT1, SOAT2, SOBP, SOCS1,SOCS2, SOCS3, SOCS4, SOCS5, SOCS6, SOCS7, SOD1, SOD2, SOD3, SOGA1,SOGA3, SOHLH1, SOHLH2, SON, SORBS1, SORBS2, SORBS3, SORCS1, SORCS2,SORCS3, SORD, SORL1, SORT1, SOS1, SOS2, SOST, SOSTDC1, SOWAHA, SOWAHB,SOWAHC, SOWAHD, SOX1, SOX10, SOX11, SOX12, SOX13, SOX14, SOX15, SOX17,SOX18, SOX2, SOX21, SOX3, SOX30, SOX4, SOX5, SOX6, SOX7, SOX8, SOX9,SP1, SP100, SP110, SP140, SP140L, SP2, SP3, SP4, SP5, SP6, SP7, SP8,SP9, SPA17, SPAAR, SPACA1, SPACA3, SPACA4, SPACA5, SPACA5B, SPACA6,SPACA7, SPACA9, SPAG1, SPAG11A, SPAG11B, SPAG16, SPAG17, SPAG4, SPAG5,SPAG6, SPAG7, SPAG8, SPAG9, SPAM1, SPANXA1, SPANXA2, SPANXB1, SPANXC,SPANXD, SPANXN1, SPANXN2, SPANXN3, SPANXN4, SPANXN5, SPARC, SPARCL1,SPART, SPAST, SPATA1, SPATA12, SPATA13, SPATA16, SPATA17, SPATA18,SPATA19, SPATA2, SPATA20, SPATA21, SPATA22, SPATA24, SPATA25, SPATA2L,SPATA3, SPATA31A1, SPATA31A3, SPATA31A5, SPATA31A6, SPATA31A7,SPATA31D1, SPATA31D3, SPATA31D4, SPATA31E1, SPATA32, SPATA33, SPATA4,SPATA45, SPATA46, SPATA5, SPATA5L1, SPATA6, SPATA6L, SPATA7, SPATA8,SPATA9, SPATC1, SPATC1L, SPATS1, SPATS2, SPATS2L, SPC24, SPC25, SPCS1,SPCS2, SPCS3, SPDEF, SPDL1, SPDYA, SPDYC, SPDYE1, SPDYE16, SPDYE2,SPDYE2B, SPDYE3, SPDYE4, SPDYE5, SPDYE6, SPECC1, SPECC1L,SPECC1L-ADORA2A, SPEF1, SPEF2, SPEG, SPEM1, SPEN, SPERT, SPESP1, SPG11,SPG21, SPG7, SPHAR, SPHK1, SPHK2, SPHKAP, SPI1, SPIB, SPIC, SPICE1,SPIDR, SPIN1, SPIN2A, SPIN2B, SPIN3, SPIN4, SPINK1, SPINK13, SPINK14,SPINK2, SPINK4, SPINK5, SPINK6, SPINK7, SPINK8, SPINK9, SPINT1, SPINT2,SPINT3, SPINT4, SPIREL SPIRE2, SPN, SPNS1, SPNS2, SPNS3, SPO11, SPOCD1,SPOCK1, SPOCK2, SPOCK3, SPON1, SPON2, SPOP, SPOPL, SPOUT1, SPP1, SPP2,SPPL2A, SPPL2B, SPPL2C, SPPL3, SPR, SPRED1, SPRED2, SPRED3, SPRN,SPRR1A, SPRR1B, SPRR2A, SPRR2B, SPRR2D, SPRR2E, SPRR2F, SPRR2G, SPRR3,SPRR4, SPRR5, SPRTN, SPRY1, SPRY2, SPRY3, SPRY4, SPRYD3, SPRYD4, SPRYD7,SPSB1, SPSB2, SPSB3, SPSB4, SPTA1, SPTAN1, SPTB, SPTBN1, SPTBN2, SPTBN4,SPTBN5, SPTLC1, SPTLC2, SPTLC3, SPTSSA, SPTSSB, SPTY2D1, SPTY2D1-AS1,SPX, SPZ1, SQLE, SQOR, SQSTM1, SRA1, SRBD1, SRC, SRCAP, SRCIN1, SRD5A1,SRD5A2, SRD5A3, SREBF1, SREBF2, SREK1, SREK1IP1, SRF, SRFBP1, SRGAP1,SRGAP2, SRGAP2B, SRGAP2C, SRGAP3, SRGN, SRI, SRL, SRM, SRMS, SRP14,SRP19, SRP54, SRP68, SRP72, SRP9, SRPK1, SRPK2, SRPK3, SRPRA, SRPRB,SRPX, SRPX2, SRR, SRRD, SRRM1, SRRM2, SRRM3, SRRM4, SRRM5, SRRT, SRSF1,SRSF10, SRSF11, SRSF12, SRSF2, SRSF3, SRSF4, SRSF5, SRSF6, SRSF7, SRSF8,SRSF9, SRXN1, SRY, SS18, SS18L1, SS18L2, SSB, SSBP1, SSBP2, SSBP3,SSBP4, SSC4D, SSC5D, SSFA2, SSH1, SSH2, SSH3, SSMEM1, SSNA1, SSPN, SSPO,SSR1, SSR2, SSR3, SSR4, SSRP1, SSSCA1, SST, SSTR1, SSTR2, SSTR3, SSTR4,SSTR5, SSU72, SSU72P8, SSUH2, SSX1, SSX2, SSX2B, SSX2IP, SSX3, SSX4,SSX4B, SSX5, SSX7, ST13, ST14, ST18, ST20, ST20-MTHFS, ST3GAL1, ST3GAL2,ST3GAL3, ST3GAL4, ST3GAL5, ST3GAL6, ST5, ST6GAL1, ST6GAL2, ST6GALNAC1,ST6GALNAC2, ST6GALNAC3, ST6GALNAC4, ST6GALNAC5, ST6GALNAC6, ST7, ST7L,ST8SIA1, ST8SIA2, ST8SIA3, ST8SIA4, ST8SIA5, ST8SIA6, STAB1, STAB2,STAC, STAC2, STAC3, STAG1, STAG2, STAG3, STAM, STAM2, STAMBP, STAMBPL1,STAP1, STAP2, STAR, STARD10, STARD13, STARD3, STARD3NL, STARD4, STARD5,STARD6, STARD7, STARD8, STARD9, STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, STAT6, STATH, STAU1, STAU2, STBD1, STC1, STC2, STEAP1, STEAP1B,STEAP2, STEAP3, STEAP4, STH, STIL, STIM1, STIM2, STIP1, STK10, STK11,STK11IP, STK16, STK17A, STK17B, STK19, STK24, STK25, STK26, STK3, STK31,STK32A, STK32B, STK32C, STK33, STK35, STK36, STK38, STK38L, STK39, STK4,STK40, STKLD1, STMN1, STMN2, STMN3, STMN4, STMND1, STN1, STOM, STOML1,STOML2, STOML3, STON1, STON1-GTF2A1L, STON2, STOX1, STOX2, STPG1, STPG2,STPG3, STPG4, STRA6, STRA8, STRADA, STRADB, STRAP, STRBP, STRC, STRIP1,STRIP2, STRN, STRN3, STRN4, STS, STT3A, STT3B, STUB1, STUM, STX10,STX11, STX12, STX16, STX16-NPEPL1, STX17, STX18, STX19, STX1A, STX1B,STX2, STX3, STX4, STX5, STX6, STX7, STX8, STXBP1, STXBP2, STXBP3,STXBP4, STXBP5, STXBP5L, STXBP6, STYK1, STYX, STYXL1, SUB1, SUCLA2,SUCLG1, SUCLG2, SUCNR1, SUCO, SUDS3, SUFU, SUGCT, SUGP1, SUGP2, SUGT1,SULF1, SULF2, SULT1A1, SULT1A2, SULT1A3, SULT1A4, SULT1B1, SULT1C2,SULT1C3, SULT1C4, SULT1E1, SULT2A1, SULT2B1, SULT4A1, SULT6B1, SUMF1,SUMF2, SUMO1, SUMO2, SUMO3, SUMO4, SUN1, SUN2, SUN3, SUN5, SUOX,SUPT16H, SUPT20H, SUPT3H, SUPT4H1, SUPT5H, SUPT6H, SUPT7L, SUPV3L1,SURF1, SURF2, SURF4, SURF6, SUSD1, SUSD2, SUSD3, SUSD4, SUSD5, SUSD6,SUV39H1, SUV39H2, SUZ12, SV2A, SV2B, SV2C, SVBP, SVEP1, SVIL, SVIP,SVOP, SVOPL, SWAP70, SWI5, SWSAP1, SWT1, SYAP1, SYBU, SYCE1, SYCE1L,SYCE2, SYCE3, SYCN, SYCP1, SYCP2, SYCP2L, SYCP3, SYDE1, SYDE2, SYF2,SYK, SYMPK, SYN1, SYN2, SYN3, SYNC, SYNCRIP, SYNDIG1, SYNDIG1L, SYNE1,SYNE2, SYNE3, SYNE4, SYNGAP1, SYNGR1, SYNGR2, SYNGR3, SYNGR4, SYNJ1,SYNJ2, SYNJ2BP, SYNJ2BP-COX16, SYNM, SYNPO, SYNPO2, SYNPO2L, SYNPR,SYNRG, SYP, SYPL1, SYPL2, SYS1, SYS1-DBNDD2, SYT1, SYT10, SYT11, SYT12,SYT13, SYT14, SYT15, SYT16, SYT17, SYT2, SYT3, SYT4, SYT5, SYT6, SYT7,SYT8, SYT9, SYTL1, SYTL2, SYTL3, SYTL4, SYTL5, SYVN1, SZRD1, SZT2, T,TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, TAAR9, TAB1, TAB2, TAB3, TAC1, TAC3,TAC4, TACC1, TACC2, TACC3, TAC01, TACR1, TACR2, TACR3, TACSTD2, TADA1,TADA2A, TADA2B, TADA3, TAF1, TAF10, TAF11, TAF12, TAF13, TAF15, TAF1A,TAF1B, TAF1C, TAF1D, TAF1L, TAF2, TAF3, TAF4, TAF4B, TAF5, TAF5L, TAF6,TAF6L, TAF7, TAF7L, TAF8, TAF9, TAF9B, TAGAP, TAGLN, TAGLN2, TAGLN3,TAL1, TAL2, TALDO1, TAMM41, TANC1, TANC2, TANGO2, TANGO6, TANK, TAOK1,TAOK2, TAOK3, TAP1, TAP2, TAPBP, TAPBPL, TAPT1, TARBP1, TARBP2, TARDBP,TARM1, TARS, TARS2, TARSL2, TAS1R1, TAS1R2, TAS1R3, TAS2R1, TAS2R10,TAS2R13, TAS2R14, TAS2R16, TAS2R19, TAS2R20, TAS2R3, TAS2R30, TAS2R31,TAS2R38, TAS2R39, TAS2R4, TAS2R40, TAS2R41, TAS2R42, TAS2R43, TAS2R46,TAS2R5, TAS2R50, TAS2R60, TAS2R7, TAS2R8, TAS2R9, TASP1, TAT, TATDN1,TATDN2, TATDN3, TAX1BP1, TAX1BP3, TAZ, TBATA, TBC1D1, TBC1D10A,TBC1D10B, TBC1D10C, TBC1D12, TBC1D13, TBC1D14, TBC1D15, TBC1D16,TBC1D17, TBC1D19, TBC1D2, TBC1D20, TBC1D21, TBC1D22A, TBC1D22B, TBC1D23,TBC1D24, TBC1D25, TBC1D26, TBC1D28, TBC1D29, TBC1D2B, TBC1D3, TBC1D30,TBC1D31, TBC1D32, TBC1D3B, TBC1D3C, TBC1D3D, TBC1D3E, TBC1D3F, TBC1D3G,TBC1D3H, TBC1D3I, TBC1D3K, TBC1D3L, TBC1D4, TBC1D5, TBC1D7, TBC1D8,TBC1D8B, TBC1D9, TBC1D9B, TBCA, TBCB, TBCC, TBCCD1, TBCD, TBCE, TBCEL,TBCK, TBK1, TBKBP1, TBL1X, TBL1XR1, TBL1Y, TBL2, TBL3, TBP, TBPL1,TBPL2, TBR1, TBRG1, TBRG4, TBX1, TBX10, TBX15, TBX18, TBX19, TBX2,TBX20, TBX21, TBX22, TBX3, TBX4, TBX5, TBX6, TBXA2R, TBXAS1, TC2N,TCAF1, TCAF2, TCAIM, TCAP, TCEA1, TCEA2, TCEA3, TCEAL1, TCEAL2, TCEAL3,TCEAL4, TCEAL5, TCEAL6, TCEAL7, TCEAL8, TCEAL9, TCEANC, TCEANC2, TCERG1,TCERG1L, TCF12, TCF15, TCF19, TCF20, TCF21, TCF23, TCF24, TCF25, TCF3,TCF4, TCF7, TCF7L1, TCF7L2, TCFL5, TCHH, TCHHL1, TCHP, TCIRG1, TCL1A,TCL1B, TCN1, TCN2, TCOF1, TCP1, TCP10, TCP10L, TCP10L2, TCP11, TCP11L1,TCP11L2, TCP11X2, TCTA, TCTE1, TCTE3, TCTEX1D1, TCTEX1D2, TCTEX1D4,TCTN1, TCTN2, TCTN3, TDG, TDGF1, TDO2, TDP1, TDP2, TDRD1, TDRD10,TDRD12, TDRD15, TDRD3, TDRD5, TDRD6, TDRD7, TDRD9, TDRKH, TDRP, TEAD1,TEAD2, TEAD3, TEAD4, TEC, TECPR1, TECPR2, TECR, TECRL, TECTA, TECTB,TEDDM1, TEF, TEFM, TEK, TEKT1, TEKT2, TEKT3, TEKT4, TEKT5, TELO2, TEN1,TEN1-CDK3, TENM1, TENM2, TENM3, TENM4, TEP1, TEPP, TEPSIN, TERB1, TERB2,TERF1, TERF2, TERF2IP, TERT, TES, TESC, TESK1, TESK2, TESMIN, TESPA1,TET1, TET2, TET3, TEX10, TEX101, TEX11, TEX12, TEX13A, TEX13B, TEX13C,TEX13D, TEX14, TEX15, TEX19, TEX2, TEX22, TEX26, TEX261, TEX264, TEX28,TEX29, TEX30, TEX33, TEX35, TEX36, TEX37, TEX38, TEX43, TEX44, TEX45,TEX46, TEX47, TEX48, TEX49, TEX50, TEX51, TEX9, TF, TFAM, TFAP2A,TFAP2B, TFAP2C, TFAP2D, TFAP2E, TFAP4, TFB1M, TFB2M, TFCP2, TFCP2L1,TFDP1, TFDP2, TFDP3, TFE3, TFEB, TFEC, TFF1, TFF2, TFF3, TFG, TFIP11,TFPI, TFPI2, TFPT, TFR2, TFRC, TG, TGDS, TGFA, TGFB1, TGFB1I1, TGFB2,TGFB3, TGFBI, TGFBR1, TGFBR2, TGFBR3, TGFBR3L, TGFBRAP1, TGIF1, TGIF2,TGIF2-C20orf24, TGIF2LX, TGIF2LY, TGM1, TGM2, TGM3, TGM4, TGM5, TGM6,TGM7, TGOLN2, TGS1, TH, THADA, THAP1, THAP10, THAP11, THAP12, THAP2,THAP3, THAP4, THAP5, THAP6, THAP7, THAP8, THAP9, THBD, THBS1, THBS2,THBS3, THBS4, THEG, THEGL, THEM4, THEM5, THEM6, THEMIS, THEMIS2, THG1L,THNSL1, THNSL2, THOC1, THOC2, THOC3, TH005, THOC6, THOC7, THOP1, THPO,THRA, THRAP3, THRB, THRSP, THSD1, THSD4, THSD7A, THSD7B, THTPA, THUMPD1,THUMPD2, THUMPD3, THY1, THYN1, TIA1, TIAF1, TIAL1, TIAM1, TIAM2, TICAM1,TICAM2, TICRR, TIE1, TIFA, TIFAB, TIGAR, TIGD1, TIGD2, TIGD3, TIGD4,TIGD5, TIGD6, TIGD7, TIGIT, TIMD4, TIMELESS, TIMM10, TIMM10B, TIMM13,TIMM17A, TIMM17B, TIMM21, TIMM22, TIMM23, TIMM23B, TIMM29, TIMM44,TIMM50, TIMM8A, TIMM8B, TIMM9, TIMMDC1, TIMP1, TIMP2, TIMP3, TIMP4,TINAG, TINAGL1, TINCR, TINF2, TIPARP, TWIN, TIPRL, TIRAP, TISP43, TJAP1,TJP1, TJP2, TJP3, TK1, TK2, TKFC, TKT, TKTL1, TKTL2, TLCD1, TLCD2,TLDC1, TLDC2, TLE1, TLE2, TLE3, TLE4, TLE6, TLK1, TLK2, TLL1, TLL2,TLN1, TLN2, TLNRD1, TLR1, TLR10, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7,TLR8, TLR9, TLX1, TLX2, TLX3, TM2D1, TM2D2, TM2D3, TM4SF1, TM4SF18,TM4SF19, TM4SF19-TCTEX1D2, TM4SF20, TM4SF4, TM4SF5, TM6SF1, TM6SF2,TM7SF2, TM7SF3, TM9SF1, TM9SF2, TM9SF3, TM9SF4, TMA16, TMA7, TMBIM1,TMBIM4, TMBIM6, TMC1, TMC2, TMC3, TMC4, TMC5, TMC6, TMC7, TMC8, TMCC1,TMCC2, TMCC3, TMCO1, TMCO2, TMCO3, TMCO4, TMCO5A, TMCO6, TMED1, TMED10,TMED2, TMED3, TMED4, TMED5, TMED6, TMED7, TMED7-TICAM2, TMED8, TMED9,TMEFF1, TMEFF2, TMEM100, TMEM101, TMEM102, TMEM104, TMEM105, TMEM106A,TMEM106B, TMEM106C, TMEM107, TMEM108, TMEM109, TMEM11, TMEM110,TMEM110-MUSTN1, TMEM114, TMEM115, TMEM116, TMEM117, TMEM119, TMEM120A,TMEM120B, TMEM121, TMEM121B, TMEM123, TMEM125, TMEM126A, TMEM126B,TMEM127, TMEM128, TMEM129, TMEM130, TMEM131, TMEM131L, TMEM132A,TMEM132B, TMEM132C, TMEM132D, TMEM132E, TMEM133, TMEM134, TMEM135,TMEM136, TMEM138, TMEM139, TMEM140, TMEM141, TMEM143, TMEM144, TMEM145,TMEM147, TMEM14A, TMEM14B, TMEM14C, TMEM150A, TMEM150B, TMEM150C,TMEM151A, TMEM151B, TMEM154, TMEM155, TMEM156, TMEM158, TMEM159,TMEM160, TMEM161A, TMEM161B, TMEM163, TMEM164, TMEM165, TMEM167A,TMEM167B, TMEM168, TMEM169, TMEM17, TMEM170A, TMEM170B, TMEM171,TMEM173, TMEM174, TMEM175, TMEM176A, TMEM176B, TMEM177, TMEM178A,TMEM178B, TMEM179, TMEM179B, TMEM18, TMEM181, TMEM182, TMEM183A,TMEM184A, TMEM184B, TMEM184C, TMEM185A, TMEM185B, TMEM186, TMEM187,TMEM189, TMEM189-UBE2V1, TMEM19, TMEM190, TMEM191B, TMEM191C, TMEM192,TMEM196, TMEM198, TMEM199, TMEM2, TMEM200A, TMEM200B, TMEM200C, TMEM201,TMEM202, TMEM203, TMEM204, TMEM205, TMEM206, TMEM207, TMEM208, TMEM209,TMEM210, TMEM211, TMEM212, TMEM213, TMEM214, TMEM215, TMEM216, TMEM217,TMEM218, TMEM219, TMEM220, TMEM221, TMEM222, TMEM223, TMEM225, TMEM225B,TMEM229A, TMEM229B, TMEM230, TMEM231, TMEM232, TMEM233, TMEM234,TMEM235, TMEM236, TMEM237, TMEM238, TMEM239, TMEM240, TMEM241, TMEM242,TMEM243, TMEM244, TMEM245, TMEM246, TMEM247, TMEM248, TMEM249, TMEM25,TMEM250, TMEM251, TMEM252, TMEM253, TMEM254, TMEM255A, TMEM255B,TMEM256, TMEM256-PLSCR3, TMEM257, TMEM258, TMEM259, TMEM26, TMEM260,TMEM262, TMEM263, TMEM265, TMEM266, TMEM267, TMEM268, TMEM269, TMEM27,TMEM270, TMEM30A, TMEM30B, TMEM31, TMEM33, TMEM35A, TMEM35B, TMEM37,TMEM38A, TMEM38B, TMEM39A, TMEM39B, TMEM40, TMEM41A, TMEM41B, TMEM42,TMEM43, TMEM44, TMEM45A, TMEM45B, TMEM47, TMEM5, TMEM50A, TMEM50B,TMEM51, TMEM52, TMEM52B, TMEM53, TMEM54, TMEM55A, TMEM55B, TMEM56,TMEM56-RWDD3, TMEM57, TMEM59, TMEM59L, TMEM60, TMEM61, TMEM62, TMEM63A,TMEM63B, TMEM63C, TMEM64, TMEM65, TMEM67, TMEM68, TMEM69, TMEM70,TMEM71, TMEM72, TMEM74, TMEM74B, TMEM78, TMEM79, TMEM80, TMEM81, TMEM82,TMEM86A, TMEM86B, TMEM87A, TMEM87B, TMEM88, TMEM88B, TMEM89, TMEM8A,TMEM8B, TMEM9, TMEM91, TMEM92, TMEM94, TMEM95, TMEM97, TMEM98, TMEM99,TMEM9B, TMF1, TMIE, TMIGD1, TMIGD2, TMIGD3, TMLHE, TMOD1, TMOD2, TMOD3,TMOD4, TMPO, TMPPE, TMPRSS11A, TMPRSS11B, TMPRSS11D, TMPRSS11E,TMPRSS11F, TMPRSS12, TMPRSS13, TMPRSS15, TMPRSS2, TMPRSS3, TMPRSS4,TMPRSS4-AS1, TMPRSS5, TMPRSS6, TMPRSS7, TMPRSS9, TMSB10, TMSB15A,TMSB15B, TMSB4X, TMSB4Y, TMTC1, TMTC2, TMTC3, TMTC4, TMUB1, TMUB2, TMX1,TMX2, TMX2-CTNND1, TMX3, TMX4, TNC, TNF, TNFAIP1, TNFAIP2, TNFAIP3,TNFAIP6, TNFAIP8, TNFAIP8L1, TNFAIP8L2, TNFAIP8L3, TNFRSF10A, TNFRSF10B,TNFRSF10C, TNFRSF10D, TNFRSF11A, TNFRSF11B, TNFRSF12A, TNFRSF13B,TNFRSF13C, TNFRSF14, TNFRSF17, TNFRSF18, TNFRSF19, TNFRSF1A, TNFRSF1B,TNFRSF21, TNFRSF25, TNFRSF4, TNFRSF6B, TNFRSF8, TNFRSF9, TNFSF10,TNFSF11, TNFSF12, TNFSF12-TNFSF13, TNFSF13, TNFSF13B, TNFSF14, TNFSF15,TNFSF18, TNFSF4, TNFSF8, TNFSF9, TNIK, TNIP1, TNIP2, TNIP3, TNK1, TNK2,TNKS, TNKS1BP1, TNKS2, TNMD, TNN, TNNC1, TNNC2, TNNI1, TNNI2, TNNI3,TNNI3K, TNNT1, TNNT2, TNNT3, TNP1, TNP2, TNPO1, TNPO2, TNPO3, TNR,TNRC18, TNRC6A, TNRC6B, TNRC6C, TNS1, TNS2, TNS3, TNS4, TNXB, TOB1,TOB2, TOE1, TOGARAM1, TOGARAM2, TOLLIP, TOM1, TOM1L1, TOM1L2, TOMM20,TOMM20L, TOMM22, TOMM34, TOMM40, TOMM40L, TOMM5, TOMM6, TOMM7, TOMM70,TONSL, TOP1, TOP1MT, TOP2A, TOP2B, TOP3A, TOP3B, TOPAZ1, TOPBP1, TOPORS,TOR1A, TOR1AIP1, TOR1AIP2, TOR1B, TOR2A, TOR3A, TOR4A, TOX, TOX2, TOX3,TOX4, TP53, TP53AIP1, TP53BP1, TP53BP2, TP53I11, TP53I13, TP53I3,TP53INP1, TP53INP2, TP53RK, TP53TG3, TP53TG3B, TP53TG3C, TP53TG3D,TP53TG3E, TP53TG3F, TP53TG5, TP63, TP73, TPBG, TPBGL, TPCN1, TPCN2,TPD52, TPD52L1, TPD52L2, TPD52L3, TPGS1, TPGS2, TPH1, TPH2, TPI1, TPK1,TPM1, TPM2, TPM3, TPM4, TPMT, TPO, TPP1, TPP2, TPPP, TPPP2, TPPP3, TPR,TPRA1, TPRG1, TPRG1L, TPRKB, TPRN, TPRX1, TPSAB1, TPSB2, TPSD1, TPSG1,TPST1, TPST2, TPT1, TPTE, TPTE2, TPX2, TRA2A, TRA2B, TRABD, TRABD2A,TRABD2B, TRAC, TRADD, TRAF1, TRAF2, TRAF3, TRAF3IP1, TRAF3IP2, TRAF3IP3,TRAF4, TRAF5, TRAF6, TRAF7, TRAFD1, TRAIP, TRAJ1, TRAJ10, TRAJ11,TRAJ12, TRAJ13, TRAJ14, TRAJ16, TRAJ17, TRAJ18, TRAJ19, TRAJ2, TRAJ20,TRAJ21, TRAJ22, TRAJ23, TRAJ24, TRAJ25, TRAJ26, TRAJ27, TRAJ28, TRAJ29,TRAJ3, TRAJ30, TRAJ31, TRAJ32, TRAJ33, TRAJ34, TRAJ35, TRAJ36, TRAJ37,TRAJ38, TRAJ39, TRAJ4, TRAJ40, TRAJ41, TRAJ42, TRAJ43, TRAJ44, TRAJ45,TRAJ46, TRAJ47, TRAJ48, TRAJ49, TRAJ5, TRAJ50, TRAJ52, TRAJ53, TRAJ54,TRAJ56, TRAJ57, TRAJ58, TRAJ59, TRAJ6, TRAJ61, TRAJ7, TRAJ9, TRAK1,TRAK2, TRAM1, TRAM1L1, TRAM2, TRANK1, TRAP1, TRAPPC1, TRAPPC10,TRAPPC11, TRAPPC12, TRAPPC13, TRAPPC2, TRAPPC2L, TRAPPC3, TRAPPC3L,TRAPPC4, TRAPPC5, TRAPPC6A, TRAPPC6B, TRAPPC8, TRAPPC9, TRAT1, TRAV10,TRAV1-1, TRAV1-2, TRAV12-1, TRAV12-2, TRAV12-3, TRAV13-1, TRAV13-2,TRAV14DV4, TRAV16, TRAV17, TRAV18, TRAV19, TRAV2, TRAV20, TRAV21,TRAV22, TRAV23DV6, TRAV24, TRAV25, TRAV26-1, TRAV26-2, TRAV27,TRAV29DV5, TRAV3, TRAV30, TRAV34, TRAV36DV7, TRAV38-1, TRAV38-2DV8,TRAV39, TRAV4, TRAV40, TRAV41, TRAV5, TRAV6, TRAV7, TRAV8-1, TRAV8-2,TRAV8-3, TRAV8-4, TRAV8-6, TRAV8-7, TRAV9-1, TRAV9-2, TRBC2, TRBJ2-1,TRBJ2-2, TRBJ2-2P, TRBJ2-3, TRBJ2-4, TRBJ2-5, TRBJ2-6, TRBJ2-7,TRBV10-1, TRBV10-2, TRBV10-3, TRBV11-1, TRBV19, TRBV2, TRBV20-1,TRBV200R9-2, TRBV21OR9-2, TRBV23-1, TRBV23OR9-2, TRBV24-1, TRBV25-1,TRBV27, TRBV28, TRBV29-1, TRBV30, TRBV3-1, TRBV4-1, TRBV4-2, TRBV5-1,TRBV5-3, TRBV5-4, TRBV5-5, TRBV5-6, TRBV5-7, TRBV6-1, TRBV6-4, TRBV6-5,TRBV6-6, TRBV6-7, TRBV6-8, TRBV7-1, TRBV7-3, TRBV7-4, TRBV7-6, TRBV7-7,TRBV7-9, TRBV9, TRDC, TRDD1, TRDD2, TRDD3, TRDJ1, TRDJ2, TRDJ3, TRDJ4,TRDMT1, TRDN, TRDV1, TRDV2, TRDV3, TREH, TREM1, TREM2, TREML1, TREML2,TREML4, TRERF1, TREX1, TREX2, TRGC1, TRGC2, TRGJ1, TRGJ2, TRGJP, TRGJP1,TRGJP2, TRGV1, TRGV10, TRGV11, TRGV2, TRGV3, TRGV4, TRGV5, TRGV8, TRGV9,TRH, TRHDE, TRHR, TRIAP1, TRIB1, TRIB2, TRIB3, TRIL, TRIM10, TRIM11,TRIM13, TRIM14, TRIM15, TRIM16, TRIM16L, TRIM17, TRIM2, TRIM21, TRIM22,TRIM23, TRIM24, TRIM25, TRIM26, TRIM27, TRIM28, TRIM29, TRIM3, TRIM31,TRIM32, TRIM33, TRIM34, TRIM35, TRIM36, TRIM37, TRIM38, TRIM39,TRIM39-RPP21, TRIM4, TRIM40, TRIM41, TRIM42, TRIM43, TRIM43B, TRIM44,TRIM45, TRIM46, TRIM47, TRIM48, TRIM49, TRIM49B, TRIM49C, TRIM49D1,TRIM49D2, TRIM5, TRIM50, TRIM51, TRIM52, TRIM54, TRIM55, TRIM56, TRIM58,TRIM59, TRIM6, TRIM60, TRIM61, TRIM62, TRIM63, TRIM64, TRIM64B, TRIM64C,TRIM65, TRIM66, TRIM67, TRIM68, TRIM69, TRIM6-TRIM34, TRIM7, TRIM71,TRIM72, TRIM73, TRIM74, TRIM75P, TRIM77, TRIM8, TRIM9, TRIML1, TRIML2,TRIO, TRIOBP, TRIP10, TRIP11, TRIP12, TRIP13, TRIP4, TRIPE, TRIQK, TRIR,TRIT1, TRMO, TRMT1, TRMT10A, TRMT10B, TRMT10C, TRMT11, TRMT112, TRMT12,TRMT13, TRMT1L, TRMT2A, TRMT2B, TRMT44, TRMT5, TRMT6, TRMT61A, TRMT61B,TRMU, TRNAU1AP, TRNP1, TRNT1, TRO, TROAP, TROVE2, TRPA1, TRPC1, TRPC3,TRPC4, TRPC4AP, TRPC5, TRPC5OS, TRPC6, TRPC7, TRPM1, TRPM2, TRPM3,TRPM4, TRPM5, TRPM6, TRPM7, TRPM8, TRPS1, TRPT1, TRPV1, TRPV2, TRPV3,TRPV4, TRPV5, TRPV6, TRRAP, TRUB1, TRUB2, TSACC, TSC1, TSC2, TSC22D1,TSC22D2, TSC22D3, TSC22D4, TSEN15, TSEN2, TSEN34, TSEN54, TSFM, TSG101,TSGA10, TSGA10IP, TSGA13, TSHB, TSHR, TSHZ1, TSHZ2, TSHZ3, TSKS, TSKU,TSLP, TSN, TSNARE1, TSNAX, TSNAX-DISC1, TSNAXIP1, TSPAN1, TSPAN10,TSPAN11, TSPAN12, TSPAN13, TSPAN14, TSPAN15, TSPAN16, TSPAN17, TSPAN18,TSPAN19, TSPAN2, TSPAN3, TSPAN31, TSPAN32, TSPAN33, TSPAN4, TSPAN5,TSPAN6, TSPAN7, TSPAN8, TSPAN9, TSPEAR, TSPO, TSPO2, TSPOAP1, TSPY1,TSPY10, TSPY2, TSPY3, TSPY4, TSPY8, TSPYL1, TSPYL2, TSPYL4, TSPYL5,TSPYL6, TSR1, TSR2, TSR3, TSSC4, TSSK1B, TSSK2, TSSK3, TSSK4, TSSK6,TST, TSTA3, TSTD1, TSTD2, TSTD3, TTBK1, TTBK2, TTC1, TTC12, TTC13,TTC14, TTC16, TTC17, TTC19, TTC21A, TTC21B, TTC22, TTC23, TTC23L, TTC24,TTC25, TTC26, TTC27, TTC28, TTC29, TTC3, TTC30A, TTC30B, TTC31, TTC32,TTC33, TTC34, TTC36, TTC37, TTC38, TTC39A, TTC39B, TTC39C, TTC4, TTC5,TTC6, TTC7A, TTC7B, TTC8, TTC9, TTC9B, TTC9C, TTF1, TTF2, TTI1, TTI2,TTK, TTL, TTLL1, TTLL10, TTLL11, TTLL12, TTLL13P, TTLL2, TTLL3, TTLL4,TTLL5, TTLL6, TTLL7, TTLL8, TTLL9, TTN, TTPA, TTPAL, TTR, TTYH1, TTYH2,TTYH3, TUB, TUBA1A, TUBA1B, TUBA1C, TUBA3C, TUBA3D, TUBA3E, TUBA4A,TUBA4B, TUBA8, TUBAL3, TUBB, TUBB1, TUBB2A, TUBB2B, TUBB3, TUBB4A,TUBB4B, TUBB6, TUBB8, TUBD1, TUBE1, TUBG1, TUBG2, TUBGCP2, TUBGCP3,TUBGCP4, TUBGCP5, TUBGCP6, TUFM, TUFT1, TULP1, TULP2, TULP3, TULP4,TUNAR, TUSC1, TUSC2, TUSC3, TUSC5, TUT1, TVP23A, TVP23B, TVP23C,TVP23C-CDRT4, TWF1, TWF2, TWIST1, TWIST2, TWISTNB, TWNK, TWSG1, TXK,TXLNA, TXLNB, TXLNG, TXN, TXN2, TXNDC11, TXNDC12, TXNDC15, TXNDC16,TXNDC17, TXNDC2, TXNDC5, TXNDC8, TXNDC9, TXNIP, TXNL1, TXNL4A, TXNL4B,TXNRD1, TXNRD2, TXNRD3, TXNRD3NB, TYK2, TYMP, TYMS, TYR, TYRO3, TYROBP,TYRP1, TYSND1, TYW1, TYW1B, TYW3, TYW5, U2AF1, U2AF1L4, U2AF1L5, U2AF2,U2SURP, UACA, UAP1, UAP1L1, UBA1, UBA2, UBA3, UBA5, UBA52, UBA6, UBA7,UBAC1, UBAC2, UBALD1, UBALD2, UBAP1, UBAP1L, UBAP2, UBAP2L, UBASH3A,UBASH3B, UBB, UBC, UBD, UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3,UBE2D4, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2F-SCLY, UBE2G1, UBE2G2,UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L5P, UBE2L6, UBE2M,UBE2N, UBE2NL, UBE2O, UBE2Q1, UBE2Q2, UBE2Q2L, UBE2QL1, UBE2R2, UBE2S,UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, UBE3A, UBE3B, UBE3C, UBE3D,UBE4A, UBE4B, UBFD1, UBIAD1, UBL3, UBL4A, UBL4B, UBL5, UBL7, UBLCP1,UBN1, UBN2, UBOX5, UBP1, UBQLN1, UBQLN2, UBQLN3, UBQLN4, UBQLNL, UBR1,UBR2, UBR3, UBR4, UBR5, UBR7, UBTD1, UBTD2, UBTF, UBTFL1, UBXN1, UBXN10,UBXN11, UBXN2A, UBXN2B, UBXN4, UBXN6, UBXN7, UBXN8, UCHL1, UCHL3, UCHL5,UCK1, UCK2, UCKL1, UCMA, UCN, UCN2, UCN3, UCP1, UCP2, UCP3, UEVLD, UFC1,UFD1, UFL1, UFM1, UFSP1, UFSP2, UGCG, UGDH, UGGT1, UGGT2, UGP2, UGT1A1,UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT2A1,UGT2A2, UGT2A3, UGT2B10, UGT2B11, UGT2B15, UGT2B17, UGT2B28, UGT2B4,UGT2B7, UGT3A1, UGT3A2, UGT8, UHMK1, UHRF1, UHRF1BP1, UHRF1BP1L, UHRF2,UIMC1, ULBP1, ULBP2, ULBP3, ULK1, ULK2, ULK3, ULK4, UMAD1, UMOD, UMODL1,UMP S, UNC119, UNC119B, UNC13A, UNC13B, UNC13C, UNC13D, UNC45A, UNC45B,UNC50, UNC5A, UNC5B, UNC5C, UNC5CL, UNC5D, UNC79, UNC80, UNC93A,UNC93B1, UNCX, UNG, UNK, UNKL, UPB1, UPF1, UPF2, UPF3A, UPF3B, UPK1A,UPK1B, UPK2, UPK3A, UPK3B, UPK3BL1, UPP1, UPP2, UPRT, UQCC1, UQCC2,UQCC3, UQCR10, UQCR11, UQCRB, UQCRC1, UQCRC2, UQCRFS1, UQCRH, UQCRHL,UQCRQ, URAD, URB1, URB2, URGCP, URGCP-MRPS24, URI1, URM1, UROC1, UROD,UROS, USB1, USE1, USF1, USF2, USF3, USH1C, USH1G, USH2A, USHBP1, USMG5,USO1, USP1, USP10, USP11, USP12, USP13, USP14, USP15, USP16, USP17L1,USP17L10, USP17L11, USP17L12, USP17L13, USP17L15, USP17L17, USP17L18,USP17L19, USP17L2, USP17L20, USP17L21, USP17L22, USP17L23, USP17L24,USP17L25, USP17L26, USP17L27, USP17L28, USP17L29, USP17L3, USP17L30,USP17L4, USP17L5, USP17L7, USP17L8, USP18, USP19, USP2, USP20, USP21,USP22, USP24, USP25, USP26, USP27X, USP28, USP29, USP3, USP30, USP31,USP32, USP33, USP34, USP35, USP36, USP37, USP38, USP39, USP4, USP40,USP41, USP42, USP43, USP44, USP45, USP46, USP47, USP48, USP49, USP5,USP50, USP51, USP53, USP54, USP6, USP6NL, USP7, USP8, USP9X, USP9Y,USPL1, UST, UTF1, UTP11, UTP14A, UTP14C, UTP15, UTP18, UTP20, UTP23,UTP3, UTP4, UTP6, UTRN, UTS2, UTS2B, UTS2R, UTY, UVRAG, UVSSA, UXS1,UXT, VAC14, VAMP1, VAMP2, VAMP3, VAMP4, VAMP5, VAMP7, VAMP8, VANGL1,VANGL2, VAPA, VAPB, VARS, VARS2, VASH1, VASH2, VASN, VASP, VAT1, VAT1L,VAV1, VAV2, VAV3, VAX1, VAX2, VBP1, VCAM1, VCAN, VCL, VCP, VCPIP1,VCPKMT, VCX, VCX2, VCX3A, VCX3B, VCY, VCY1B, VDAC1, VDAC2, VDAC3, VDR,VEGFA, VEGFB, VEGFC, VEGFD, VENTX, VEPH1, VEZF1, VEZT, VGF, VGLL1,VGLL2, VGLL3, VGLL4, VHL, VHLL, VIL1, VILL, VIM, VIP, VIPAS39, VIPR1,VIPR2, VIRMA, VIT, VKORC1, VKORC1L1, VLDLR, VMA21, VMAC, VMO1, VMP1,VN1R1, VN1R2, VN1R4, VN1R5, VNN1, VNN2, VNN3, VOPP1, VPREB1, VPREB3,VPS11, VPS13A, VPS13B, VPS13C, VPS13D, VPS16, VPS18, VPS25, VPS26A,VPS26B, VPS28, VPS29, VPS33A, VPS33B, VPS35, VPS36, VPS37A, VPS37B,VPS37C, VPS37D, VPS39, VPS41, VPS45, VPS4A, VPS4B, VPS50, VPS51, VPS52,VPS53, VPS54, VPS72, VPS8, VPS9D1, VRK1, VRK2, VRK3, VRTN, VSIG1,VSIG10, VSIG10L, VSIG10L2, VSIG2, VSIG4, VSIG8, VSIR, VSNL1, VSTM1,VSTM2A, VSTM2B, VSTM2L, VSTM4, VSTM5, VSX1, VSX2, VTA1, VTCN1, VTI1A,VTI1B, VTN, VWA1, VWA2, VWA3A, VWA3B, VWA5A, VWA5B1, VWA5B2, VWA7, VWA8,VWC2, VWC2L, VWCE, VWDE, VWF, WAC, WAPL, WARS, WARS2, WAS, WASF1, WASF2,WASF3, WASHC1, WASHC2A, WASHC2C, WASHC3, WASHC4, WASHC5, WASL, WBP1,WBP11, WBP1L, WBP2, WBP2NL, WBP4, WDCP, WDFY1, WDFY2, WDFY3, WDFY4,WDHD1, WDPCP, WDR1, WDR11, WDR12, WDR13, WDR17, WDR18, WDR19, WDR20,WDR24, WDR25, WDR26, WDR27, WDR3, WDR31, WDR33, WDR34, WDR35, WDR36,WDR37, WDR38, WDR4, WDR41, WDR43, WDR44, WDR45, WDR45B, WDR46, WDR47,WDR48, WDR49, WDR5, WDR53, WDR54, WDR55, WDR59, WDR5B, WDR6, WDR60,WDR61, WDR62, WDR63, WDR64, WDR66, WDR7, WDR70, WDR72, WDR73, WDR74,WDR75, WDR76, WDR77, WDR78, WDR81, WDR82, WDR83, WDR83OS, WDR86, WDR87,WDR88, WDR89, WDR90, WDR91, WDR92, WDR93, WDR97, WDSUB1, WDTC1, WDYHV1,WEE1, WEE2, WFDC1, WFDC10A, WFDC10B, WFDC11, WFDC12, WFDC13, WFDC2,WFDC3, WFDC5, WFDC6, WFDC8, WFDC9, WFIKKN1, WFIKKN2, WFS1, WHAMM, WHRN,WIF1, WIPF1, WIPF2, WIPF3, WIPI1, WIPI2, WISP1, WISP2, WISP3, WIZ, WLS,WNK1, WNK2, WNK3, WNK4, WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT2B,WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B,WNT9A, WNT9B, WRAP53, WRAP73, WRB, WRN, WRNIP1, WSB1, WSB2, WSCD1,WSCD2, WT1, WTAP, WTH3DI, WTIP, WWC1, WWC2, WWC3, WWOX, WWP1, WWP2,WWTR1, XAB2, XAF1, XAGE1A, XAGE1B, XAGE2, XAGE3, XAGE5, XBP1, XCL1,XCL2, XCR1, XDH, XG, XIAP, XIRP1, XIRP2, XK, XKR3, XKR4, XKR5, XKR6,XKR7, XKR8, XKR9, XKRX, XPA, XPC, XPNPEP1, XPNPEP2, XPNPEP3, XPO1, XPO4,XPO5, XPO6, XPO7, XPOT, XPR1, XRCC1, XRCC2, XRCC3, XRCC4, XRCC5, XRCC6,XRN1, XRN2, XRRA1, XXYLT1, XYLB, XYLT1, XYLT2, YAE1D1, YAF2, YAP1, YARS,YARS2, YBEY, YBX1, YBX2, YBX3, YDJC, YEATS2, YEATS4, YES1, YIF1A, YIF1B,YIPF1, YIPF2, YIPF3, YIPF4, YIPF5, YIPF6, YIPF7, YJEFN3, YKT6, YLPM1,YME1L1, YOD1, YPEL1, YPEL2, YPEL3, YPEL4, YPEL5, YRDC, YTHDC1, YTHDC2,YTHDF1, YTHDF2, YTHDF3, YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ, YWHAZ, YY1,YY1AP1, YY2, Z82206.1, Z83844.1, Z84492.1, Z98749.3, Z98752.3, ZACN,ZADH2, ZAN, ZAP70, ZAR1, ZAR1L, ZBBX, ZBED1, ZBED2, ZBED3, ZBED4, ZBED5,ZBED6, ZBED6CL, ZBED8, ZBED9, ZBP1, ZBTB1, ZBTB10, ZBTB11, ZBTB12,ZBTB14, ZBTB16, ZBTB17, ZBTB18, ZBTB2, ZBTB20, ZBTB21, ZBTB22, ZBTB24,ZBTB25, ZBTB26, ZBTB3, ZBTB32, ZBTB33, ZBTB34, ZBTB37, ZBTB38, ZBTB39,ZBTB4, ZBTB40, ZBTB41, ZBTB42, ZBTB43, ZBTB44, ZBTB45, ZBTB46, ZBTB47,ZBTB48, ZBTB49, ZBTB5, ZBTB6, ZBTB7A, ZBTB7B, ZBTB7C, ZBTB8A, ZBTB8B,ZBTB8OS, ZBTB9, ZC2HC1A, ZC2HC1B, ZC2HC1C, ZC3H10, ZC3H11A, ZC3H11B,ZC3H12A, ZC3H12B, ZC3H12C, ZC3H12D, ZC3H13, ZC3H14, ZC3H15, ZC3H18,ZC3H3, ZC3H4, ZC3H6, ZC3H7A, ZC3H7B, ZC3H8, ZC3HAV1, ZC3HAV1L, ZC3HC1,ZC4H2, ZCCHC10, ZCCHC11, ZCCHC12, ZCCHC13, ZCCHC14, ZCCHC17, ZCCHC18,ZCCHC2, ZCCHC24, ZCCHC3, ZCCHC4, ZCCHC6, ZCCHC7, ZCCHC8, ZCCHC9, ZCRB1,ZCWPW1, ZCWPW2, ZDBF2, ZDHHC1, ZDHHC11, ZDHHC 11B, ZDHHC12, ZDHHC 13,ZDHHC 14, ZDHHC 15, ZDHHC16, ZDHHC17, ZDHHC18, ZDHHC19, ZDHHC2, ZDHHC20,ZDHHC21, ZDHHC22, ZDHHC23, ZDHHC24, ZDHHC3, ZDHHC4, ZDHHC5, ZDHHC6,ZDHHC7, ZDHHC8, ZDHHC9, ZEB1, ZEB2, ZER1, ZFAND1, ZFAND2A, ZFAND2B,ZFAND3, ZFAND4, ZFAND5, ZFAND6, ZFAT, ZFC3H1, ZFHX2, ZFHX3, ZFHX4, ZFP1,ZFP14, ZFP2, ZFP28, ZFP3, ZFP30, ZFP36, ZFP36L1, ZFP36L2, ZFP37, ZFP41,ZFP42, ZFP57, ZFP62, ZFP64, ZFP69, ZFP69B, ZFP82, ZFP90, ZFP91,ZFP91-CNTF, ZFP92, ZFPL1, ZFPM1, ZFPM2, ZFR, ZFR2, ZFX, ZFY, ZFYVE1,ZFYVE16, ZFYVE19, ZFYVE21, ZFYVE26, ZFYVE27, ZFYVE28, ZFYVE9, ZG16,ZG16B, ZGLP1, ZGPAT, ZGRF1, ZHX1, ZHX1-C8orf76, ZHX2, ZHX3, ZIC1, ZIC2,ZIC3, ZIC4, ZIC5, ZIK1, ZIM2, ZIM3, ZKSCAN1, ZKSCAN2, ZKSCAN3, ZKSCAN4,ZKSCAN5, ZKSCAN7, ZKSCAN8, ZMAT1, ZMAT2, ZMAT3, ZMAT4, ZMAT5, ZMIZ1,ZMIZ2, ZMPSTE24, ZMYM1, ZMYM2, ZMYM3, ZMYM4, ZMYM5, ZMYM6, ZMYND10,ZMYND11, ZMYND12, ZMYND15, ZMYND19, ZMYND8, ZNF10, ZNF100, ZNF101,ZNF106, ZNF107, ZNF112, ZNF114, ZNF117, ZNF12, ZNF121, ZNF124, ZNF131,ZNF132, ZNF133, ZNF134, ZNF135, ZNF136, ZNF138, ZNF14, ZNF140, ZNF141,ZNF142, ZNF143, ZNF146, ZNF148, ZNF154, ZNF155, ZNF157, ZNF16, ZNF160,ZNF165, ZNF169, ZNF17, ZNF174, ZNF175, ZNF177, ZNF18, ZNF180, ZNF181,ZNF182, ZNF184, ZNF185, ZNF189, ZNF19, ZNF195, ZNF197, ZNF2, ZNF20,ZNF200, ZNF202, ZNF205, ZNF207, ZNF208, ZNF211, ZNF212, ZNF213, ZNF214,ZNF215, ZNF217, ZNF219, ZNF22, ZNF221, ZNF222, ZNF223, ZNF224, ZNF225,ZNF226, ZNF227, ZNF229, ZNF23, ZNF230, ZNF232, ZNF233, ZNF234, ZNF235,ZNF236, ZNF239, ZNF24, ZNF248, ZNF25, ZNF250, ZNF251, ZNF253, ZNF254,ZNF256, ZNF257, ZNF26, ZNF260, ZNF263, ZNF264, ZNF266, ZNF267, ZNF268,ZNF273, ZNF274, ZNF275, ZNF276, ZNF277, ZNF28, ZNF280A, ZNF280B,ZNF280C, ZNF280D, ZNF281, ZNF282, ZNF283, ZNF284, ZNF285, ZNF286A,ZNF286B, ZNF287, ZNF292, ZNF296, ZNF3, ZNF30, ZNF300, ZNF302, ZNF304,ZNF311, ZNF316, ZNF317, ZNF318, ZNF319, ZNF32, ZNF320, ZNF322, ZNF324,ZNF324B, ZNF326, ZNF329, ZNF330, ZNF331, ZNF333, ZNF334, ZNF335, ZNF337,ZNF33A, ZNF33B, ZNF34, ZNF341, ZNF343, ZNF345, ZNF346, ZNF347, ZNF35,ZNF350, ZNF354A, ZNF354B, ZNF354C, ZNF358, ZNF362, ZNF365, ZNF366,ZNF367, ZNF37A, ZNF382, ZNF383, ZNF384, ZNF385A, ZNF385B, ZNF385C,ZNF385D, ZNF391, ZNF394, ZNF395, ZNF396, ZNF397, ZNF398, ZNF404, ZNF407,ZNF408, ZNF41, ZNF410, ZNF414, ZNF415, ZNF416, ZNF417, ZNF418, ZNF419,ZNF420, ZNF423, ZNF425, ZNF426, ZNF428, ZNF429, ZNF43, ZNF430, ZNF431,ZNF432, ZNF433, ZNF436, ZNF438, ZNF439, ZNF44, ZNF440, ZNF441, ZNF442,ZNF443, ZNF444, ZNF445, ZNF446, ZNF449, ZNF45, ZNF451, ZNF454, ZNF460,ZNF461, ZNF462, ZNF467, ZNF468, ZNF469, ZNF470, ZNF471, ZNF473, ZNF474,ZNF479, ZNF48, ZNF480, ZNF483, ZNF484, ZNF485, ZNF486, ZNF487, ZNF488,ZNF490, ZNF491, ZNF492, ZNF493, ZNF496, ZNF497, ZNF500, ZNF501, ZNF502,ZNF503, ZNF506, ZNF507, ZNF510, ZNF511, ZNF512, ZNF512B, ZNF513, ZNF514,ZNF516, ZNF517, ZNF518A, ZNF518B, ZNF519, ZNF521, ZNF524, ZNF525,ZNF526, ZNF527, ZNF528, ZNF529, ZNF530, ZNF532, ZNF534, ZNF536, ZNF540,ZNF541, ZNF543, ZNF544, ZNF546, ZNF547, ZNF548, ZNF549, ZNF550, ZNF551,ZNF552, ZNF554, ZNF555, ZNF556, ZNF557, ZNF558, ZNF559, ZNF559-ZNF177,ZNF560, ZNF561, ZNF562, ZNF563, ZNF564, ZNF565, ZNF566, ZNF567, ZNF568,ZNF569, ZNF57, ZNF570, ZNF571, ZNF572, ZNF573, ZNF574, ZNF575, ZNF576,ZNF577, ZNF578, ZNF579, ZNF580, ZNF581, ZNF582, ZNF583, ZNF584, ZNF585A,ZNF585B, ZNF586, ZNF587, ZNF587B, ZNF589, ZNF592, ZNF593, ZNF594,ZNF595, ZNF596, ZNF597, ZNF598, ZNF599, ZNF600, ZNF605, ZNF606, ZNF607,ZNF608, ZNF609, ZNF610, ZNF611, ZNF613, ZNF614, ZNF615, ZNF616, ZNF618,ZNF619, ZNF620, ZNF621, ZNF622, ZNF623, ZNF624, ZNF625, ZNF625-ZNF20,ZNF626, ZNF627, ZNF628, ZNF629, ZNF630, ZNF638, ZNF639, ZNF641, ZNF644,ZNF645, ZNF646, ZNF648, ZNF649, ZNF652, ZNF653, ZNF654, ZNF655, ZNF658,ZNF66, ZNF660, ZNF662, ZNF664, ZNF665, ZNF667, ZNF668, ZNF669, ZNF670,ZNF670-ZNF695, ZNF671, ZNF672, ZNF674, ZNF675, ZNF676, ZNF677, ZNF678,ZNF679, ZNF680, ZNF681, ZNF682, ZNF683, ZNF684, ZNF687, ZNF688, ZNF689,ZNF69, ZNF691, ZNF692, ZNF695, ZNF696, ZNF697, ZNF699, ZNF7, ZNF70,ZNF700, ZNF701, ZNF703, ZNF704, ZNF705A, ZNF705B, ZNF705D, ZNF705E,ZNF705G, ZNF706, ZNF707, ZNF708, ZNF709, ZNF71, ZNF710, ZNF711, ZNF713,ZNF714, ZNF716, ZNF717, ZNF718, ZNF720, ZNF721, ZNF724, ZNF726, ZNF727,ZNF728, ZNF729, ZNF730, ZNF732, ZNF735, ZNF736, ZNF737, ZNF738, ZNF74,ZNF740, ZNF746, ZNF747, ZNF749, ZNF750, ZNF75A, ZNF75D, ZNF76, ZNF761,ZNF763, ZNF764, ZNF765, ZNF766, ZNF768, ZNF77, ZNF770, ZNF771, ZNF772,ZNF773, ZNF774, ZNF775, ZNF776, ZNF777, ZNF778, ZNF780A, ZNF780B,ZNF781, ZNF782, ZNF783, ZNF784, ZNF785, ZNF786, ZNF787, ZNF788, ZNF789,ZNF79, ZNF790, ZNF791, ZNF792, ZNF793, ZNF799, ZNF8, ZNF80, ZNF800,ZNF804A, ZNF804B, ZNF805, ZNF808, ZNF81, ZNF813, ZNF814, ZNF816,ZNF816-ZNF321P, ZNF821, ZNF823, ZNF827, ZNF829, ZNF83, ZNF830, ZNF831,ZNF835, ZNF836, ZNF837, ZNF839, ZNF84, ZNF841, ZNF843, ZNF844, ZNF845,ZNF846, ZNF85, ZNF850, ZNF852, ZNF853, ZNF860, ZNF862, ZNF865, ZNF878,ZNF879, ZNF880, ZNF883, ZNF888, ZNF891, ZNF90, ZNF91, ZNF92, ZNF93,ZNF98, ZNF99, ZNFX1, ZNHIT1, ZNHIT2, ZNHIT3, ZNHIT6, ZNRD1, ZNRF1,ZNRF2, ZNRF3, ZNRF4, ZP1, ZP2, ZP3, ZP4, ZPBP, ZPBP2, ZPLD1, ZPR1,ZRANB1, ZRANB2, ZRANB3, ZRSR1, ZRSR2, ZSCAN1, ZSCAN10, ZSCAN12, ZSCAN16,ZSCAN18, ZSCAN2, ZSCAN20, ZSCAN21, ZSCAN22, ZSCAN23, ZSCAN25, ZSCAN26,ZSCAN29, ZSCAN30, ZSCAN31, ZSCAN32, ZSCAN4, ZSCAN5A, ZSCAN5B, ZSCAN5C,ZSCAN9, ZSWIM1, ZSWIM2, ZSWIM3, ZSWIM4, ZSWIM5, ZSWIM6, ZSWIM7, ZSWIM8,ZUFSP, ZW10, ZWILCH, ZWINT, ZXDA, ZXDB, ZXDC, ZYG11A, ZYG11B, ZYX,ZZEF1, and ZZZ3.

In certain embodiments, TBM is a target binding moiety that binds to oneor more of SMARCA2, SMARCA4, and PBRM1. In certain embodiments, TBM is atarget binding moiety that binds to MERTK.

Protein Level Control

This description also provides methods for the control of protein levelswith a cell. This is based on the use of compounds as described herein,which are known to interact with a specific target protein such thatdegradation of a target protein in vivo will result in the control ofthe amount of protein in a biological system, preferably to a particulartherapeutic benefit.

Furthermore, the invention provides the use of a compound according tothe definitions herein, or a pharmaceutically acceptable salt, or ahydrate or solvate thereof for the preparation of a medicament for thetreatment of an autoimmune disorder, an inflammatory disorder, or aproliferative disorder, or a disorder commonly occurring in connectionwith transplantation.

Combination Therapies

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this invention. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.”

In certain embodiments, a provided combination, or composition thereof,is administered in combination with another therapeutic agent.

In some embodiments, the present invention provides a method of treatinga disclosed disease or condition comprising administering to a patientin need thereof an effective amount of a compound disclosed herein or apharmaceutically acceptable salt thereof and co-administeringsimultaneously or sequentially an effective amount of one or moreadditional therapeutic agents, such as those described herein. In someembodiments, the method includes co-administering one additionaltherapeutic agent. In some embodiments, the method includesco-administering two additional therapeutic agents. In some embodiments,the combination of the disclosed compound and the additional therapeuticagent or agents acts synergistically.

Examples of agents the combinations of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for HIV such asritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa,entacapone, ropinrole, pramipexole, bromocriptine, pergolide,trihexephendyl, and amantadine; agents for treating Multiple Sclerosis(MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, andmitoxantrone; treatments for asthma such as albuterol and Singulair®;agents for treating schizophrenia such as zyprexa, risperdal, seroquel,and haloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; agents thatprolong or improve pharmacokinetics such as cytochrome P450 inhibitors(i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g.,ketoconazole and ritonavir), and agents for treating immunodeficiencydisorders such as gamma globulin.

In certain embodiments, combination therapies of the present invention,or a pharmaceutically acceptable composition thereof, are administeredin combination with a monoclonal antibody or an siRNA therapeutic.

Those additional agents may be administered separately from a providedcombination therapy, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a combination ofthe present invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

In one embodiment, the present invention provides a compositioncomprising a provided compound and one or more additional therapeuticagents. The therapeutic agent may be administered together with aprovided compound or may be administered prior to or followingadministration of a provided compound. Suitable therapeutic agents aredescribed in further detail below. In certain embodiments, a providedcompound may be administered up to 5 minutes, 10 minutes, 15 minutes, 30minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours,8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. Inother embodiments, a provided compound may be administered up to 5minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours,12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hoursfollowing the therapeutic agent.

In another embodiment, the present invention provides a method oftreating an inflammatory disease, disorder or condition by administeringto a patient in need thereof a provided compound and one or moreadditional therapeutic agents. Such additional therapeutic agents may besmall molecules or recombinant biologic agents and include, for example,acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, probenecid,allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®),antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine(Aralen®), methotrexate (Rheumatrex®), gold salts such as goldthioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin(Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine(Imuran®), cyclophosphami de (Cytoxan®), chlorambucil (Leukeran®),cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agentssuch as etanercept (Enbrel®), infliximab (Remicade®), golimumab(Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®),“anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such astofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®), “anti-IL-6” agents such astocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc®or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot®, anticholinergics or antispasmodics such as dicyclomine(Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA,Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®),pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®),salmeterol xinafoate (Serevent®) and formoterol (Foradil®),anticholinergic agents such as ipratropium bromide (Atrovent®) andtiotropium (Spiriva®), inhaled corticosteroids such as beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), andflunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium(Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®,Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such asomalizumab (Xolair®), nucleoside reverse transcriptase inhibitors suchas zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine(Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine(Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®),lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine(Hivid®), non-nucleoside reverse transcriptase inhibitors such asdelavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®)and etravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), doxorubicin(Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), anddexamethasone (Decadron®) in combination with lenalidomide (Revlimid®),or any combination(s) thereof.

In another embodiment, the present invention provides a method oftreating rheumatoid arthritis comprising administering to a patient inneed thereof a provided compound and one or more additional therapeuticagents selected from non-steroidal anti-inflammatory drugs (NSAIDS) suchas aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,corticosteroids such as prednisone, prednisolone, methylprednisolone,hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarialssuch as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®),methotrexate (Rheumatrex®), gold salts such as gold thioglucose(Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®),D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®),cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine(Sandimmune®), leflunomide (Arava®) and “anti-TNF” agents such asetanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®),certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1”agents such as anakinra (Kineret®) and rilonacept (Arcalyst®),antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such asabatacept (Orencia®) and “anti-IL-6” agents such as tocilizumab(Actemra®).

In some embodiments, the present invention provides a method of treatingosteoarthritis comprising administering to a patient in need thereof aprovided compound and one or more additional therapeutic agents selectedfrom acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) suchas aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) andmonoclonal antibodies such as tanezumab.

In some embodiments, the present invention provides a method of treatingsystemic lupus erythematosus comprising administering to a patient inneed thereof a provided compound and one or more additional therapeuticagents selected from acetaminophen, non-steroidal anti-inflammatorydrugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®)and celecoxib, corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, antimalarials such ashydroxychloroquine (Plaquenil®) and chloroquine (Aralen®),cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine(Imuran®) and anticoagulants such as heparin (Calcinparine® orLiquaemin®) and warfarin (Coumadin®).

In some embodiments, the present invention provides a method of treatingCrohn's disease, ulcerative colitis, or inflammatory bowel diseasecomprising administering to a patient in need thereof a providedcompound and one or more additional therapeutic agents selected frommesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such asdiphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid bindingagents such as cholestyramine, alosetron (Lotronex®), lubiprostone(Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol(MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics orantispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies,steroids, and antibiotics such as Flagyl or ciprofloxacin.

In some embodiments, the present invention provides a method of treatingasthma comprising administering to a patient in need thereof a providedcompound and one or more additional therapeutic agents selected fromSingulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil®HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterolacetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterolxinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agentssuch as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®),inhaled corticosteroids such as prednisone, prednisolone, beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®),flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolynsodium (Intal®), methylxanthines such as theophylline (Theo-Dur®,Theolair®, Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, and IgEantibodies such as omalizumab (Xolair®).

In some embodiments, the present invention provides a method of treatingCOPD comprising administering to a patient in need thereof a providedcompound and one or more additional therapeutic agents selected frombeta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA),levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate(Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate(Serevent®) and formoterol (Foradil®), anticholinergic agents such asipratropium bromide (Atrovent®) and tiotropium (Spiriva®),methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-Bid®,Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such asprednisone, prednisolone, beclomethasone dipropionate (Beclovent®,Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone(Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®,Symbicort®, and Dulera®,

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a provided compound and one or more additionaltherapeutic agents selected from rituximab (Rituxan®), cyclophosphami de(Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®),prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, andcombinations thereof.

In another embodiment, the present invention provides a method oftreating a solid tumor comprising administering to a patient in needthereof a provided compound and one or more additional therapeuticagents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®),doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, ahedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor,a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a provided compound and a Hedgehog (Hh)signaling pathway inhibitor. In some embodiments, the hematologicalmalignancy is DLBCL (Ramirez et al “Defining causative factorscontributing in the activation of hedgehog signaling in diffuse largeB-cell lymphoma” Leuk. Res. (2012), published online July 17, andincorporated herein by reference in its entirety).

In another embodiment, the present invention provides a method oftreating diffuse large B-cell lymphoma (DLBCL) comprising administeringto a patient in need thereof a provided compound and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphami de (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, andcombinations thereof.

In another embodiment, the present invention provides a method oftreating multiple myeloma comprising administering to a patient in needthereof a provided compound and one or more additional therapeuticagents selected from bortezomib (Velcade®), and dexamethasone(Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYKinhibitor in combination with lenalidomide (Revlimid®).

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound and a BTK inhibitor,wherein the disease is selected from inflammatory bowel disease,arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathicthrombocytopenic purpura (ITP), rheumatoid arthritis, psoriaticarthritis, osteoarthritis, Still's disease, juvenile arthritis,diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis,Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiplesclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barresyndrome, acute disseminated encephalomyelitis, Addison's disease,opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipidantibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmunegastritis, pernicious anemia, celiac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behcet's disease,chronic fatigue, dysautonomia, membranous glomerulonephropathy,endometriosis, interstitial cystitis, pemphigus vulgaris, bullouspemphigoid, neuromyotonia, scleroderma, vulvodynia, a hyperproliferativedisease, rejection of transplanted organs or tissues, AcquiredImmunodeficiency Syndrome (AIDS, also known as HIV), type 1 diabetes,graft versus host disease, transplantation, transfusion, anaphylaxis,allergies (e.g., allergies to plant pollens, latex, drugs, foods, insectpoisons, animal hair, animal dander, dust mites, or cockroach calyx),type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, andatopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma,allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis,dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,hidradenitis suppurativa, immunoglobulin A nephropathy, interstitiallung disease, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferativedisorder, e.g., diffuse large B cell lymphoma, follicular lymphoma,chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acutelymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplamacyticlymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma,multiple myeloma (also known as plasma cell myeloma), non-Hodgkin'slymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone Bcell lymphoma, nodal marginal zone B cell lymphoma, mantle celllymphoma, mediastinal (thymic) large B cell lymphoma, intravascularlarge B cell lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, or lymphomatoid granulomatosis, breast cancer,prostate cancer, or cancer of the mast cells (e.g., mastocytoma, mastcell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer,colorectal cancer, pancreatic cancer, diseases of the bone and jointsincluding, without limitation, rheumatoid arthritis, seronegativespondyloarthropathies (including ankylosing spondylitis, psoriaticarthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome,systemic sclerosis, osteoporosis, bone cancer, bone metastasis, athromboembolic disorder, (e.g., myocardial infarct, angina pectoris,reocclusion after angioplasty, restenosis after angioplasty, reocclusionafter aortocoronary bypass, restenosis after aortocoronary bypass,stroke, transitory ischemia, a peripheral arterial occlusive disorder,pulmonary embolism, deep venous thrombosis), inflammatory pelvicdisease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis,meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis,gastritis, enteritis, dermatitis, gingivitis, appendicitis,pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy,Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren'sdisease, tissue graft rejection, hyperacute rejection of transplantedorgans, asthma, allergic rhinitis, chronic obstructive pulmonary disease(COPD), autoimmune polyglandular disease (also known as autoimmunepolyglandular syndrome), autoimmune alopecia, pernicious anemia,glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma,vasculitis, autoimmune hemolytic and thrombocytopenic states,Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson'sdisease, Alzheimer's disease, diabetes, septic shock, systemic lupuserythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenilearthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura,Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto'sthyroiditis, atopic dermatitis, degenerative joint disease, vitiligo,autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease,scleroderma, mycosis fungoides, acute inflammatory responses (such asacute respiratory distress syndrome and ischemia/reperfusion injury),and Graves' disease.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound and a PI3K inhibitor,wherein the disease is selected from a cancer, a neurodegenerativedisorder, an angiogenic disorder, a viral disease, an autoimmunedisease, an inflammatory disorder, a hormone-related disease, conditionsassociated with organ transplantation, immunodeficiency disorders, adestructive bone disorder, a proliferative disorder, an infectiousdisease, a condition associated with cell death, thrombin-inducedplatelet aggregation, chronic myelogenous leukemia (CML), chroniclymphocytic leukemia (CLL), liver disease, pathologic immune conditionsinvolving T cell activation, a cardiovascular disorder, and a CNSdisorder.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound and a PI3K inhibitor,wherein the disease is selected from benign or malignant tumor,carcinoma or solid tumor of the brain, kidney (e.g., renal cellcarcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach,gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung,vagina, endometrium, cervix, testis, genitourinary tract, esophagus,larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas,multiple myeloma or gastrointestinal cancer, especially colon carcinomaor colorectal adenoma or a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, (including, for example,non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (also termedHodgkin's or Hodgkin's disease)), a mammary carcinoma, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma,melanoma, or a leukemia, diseases include Cowden syndrome,Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases inwhich the PI3K/PKB pathway is aberrantly activated, asthma of whatevertype or genesis including both intrinsic (non-allergic) asthma andextrinsic (allergic) asthma, mild asthma, moderate asthma, severeasthma, bronchitic asthma, exercise-induced asthma, occupational asthmaand asthma induced following bacterial infection, acute lung injury(ALI), adult/acute respiratory distress syndrome (ARDS), chronicobstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema,as well as exacerbation of airways hyperreactivity consequent to otherdrug therapy, in particular other inhaled drug therapy, bronchitis ofwhatever type or genesis including, but not limited to, acute,arachidic, catarrhal, croupus, chronic or phthinoid bronchitis,pneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis,Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particularmetazoan) infestation (including tropical eosinophilia),bronchopulmonary aspergillosis, polyarteritis nodosa (includingChurg-Strauss syndrome), eosinophilic granuloma and eosinophil-relateddisorders affecting the airways occasioned by drug-reaction, psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, pemphisus, epidermolysis bullosa acquisita,conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis,diseases affecting the nose including allergic rhinitis, andinflammatory disease in which autoimmune reactions are implicated orhaving an autoimmune component or etiology, including autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), systemic lupuserythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegenergranulamatosis, dermatomyositis, chronic active hepatitis, myastheniagravis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (e.g. ulcerative colitis and Crohn'sdisease), endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis and glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minal change nephropathy, restenosis, cardiomegaly, atherosclerosis,myocardial infarction, ischemic stroke and congestive heart failure,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, and cerebral ischemia, and neurodegenerativedisease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

In some embodiments the present invention provides a method of treatingor lessening the severity of a disease comprising administering to apatient in need thereof a provided compound and a Bcl-2 inhibitor,wherein the disease is an inflammatory disorder, an autoimmune disorder,a proliferative disorder, an endocrine disorder, a neurologicaldisorder, or a disorder associated with transplantation. In someembodiments, the disorder is a proliferative disorder, lupus, or lupusnephritis. In some embodiments, the proliferative disorder is chroniclymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease,small-cell lung cancer, non-small-cell lung cancer, myelodysplasticsyndrome, lymphoma, a hematological neoplasm, or solid tumor.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of anautoimmune disorder, an inflammatory disorder, a proliferative disorder,an endocrine disorder, a neurological disorder, or a disorder associatedwith transplantation. The exact amount required will vary from subjectto subject, depending on the species, age, and general condition of thesubject, the severity of the infection, the particular agent, its modeof administration, and the like. Compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofmodulating CRBN activity in a biological sample comprising the step ofcontacting said biological sample with a compound of this invention, ora composition comprising said compound.

According to another embodiment, the invention relates to a method ofbinding CRBN, or a mutant thereof, activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof biopsied material obtainedfrom a mammal or extracts thereof; and blood, saliva, urine, feces,semen, tears, or other body fluids or extracts thereof.

Binding CRBN (or a mutant thereof) activity in a biological sample isuseful for a variety of purposes that are known to one of skill in theart. Examples of such purposes include, but are not limited to,biological specimen storage and biological assays.

Another embodiment of the present invention relates to a method ofmodulating CRBN activity in a patient comprising the step ofadministering to said patient a compound of the present invention, or acomposition comprising said compound.

According to another embodiment, the invention relates to a method ofmodulating the activity of CRBN, or a mutant thereof, in a patientcomprising the step of administering to said patient a compound of thepresent invention, or a composition comprising said compound. Accordingto certain embodiments, the invention relates to a method of reversiblyor irreversibly modulating one or more of CRBN, or a mutant thereof,activity in a patient comprising the step of administering to saidpatient a compound of the present invention, or a composition comprisingsaid compound. In other embodiments, the present invention provides amethod for treating a disorder mediated by CRBN, or a mutant thereof, ina patient in need thereof, comprising the step of administering to saidpatient a compound according to the present invention orpharmaceutically acceptable composition thereof. Such disorders aredescribed in detail herein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

A compound of the current invention may also be used to advantage incombination with other therapeutic compounds. In some embodiments, theother therapeutic compounds are antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; matrixmetalloproteinase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from ConformaTherapeutics; temozolomide (Temodal®); kinesin spindle proteininhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such asARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 fromPfizer and leucovorin. The term “aromatase inhibitor” as used hereinrelates to a compound which inhibits estrogen production, for instance,the conversion of the substrates androstenedione and testosterone toestrone and estradiol, respectively. The term includes, but is notlimited to steroids, especially atamestane, exemestane and formestaneand, in particular, non-steroids, especially aminoglutethimide,roglethimide, pyridoglutethimide, trilostane, testolactone,ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestaneis marketed under the trade name Aromasin™. Formestane is marketed underthe trade name Lentaron™. Fadrozole is marketed under the trade nameAfema™. Anastrozole is marketed under the trade name Arimidex™ Letrozoleis marketed under the trade names Femara™ or Femar™. Aminoglutethimideis marketed under the trade name Orimeten™. A combination of theinvention comprising a chemotherapeutic agent which is an aromataseinhibitor is particularly useful for the treatment of hormone receptorpositive tumors, such as breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™. Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an anti estrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™). The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™) daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed. under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™. Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the AxI receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, BTK and TEC family, and/or membersof the cyclin-dependent kinase family (CDK) including staurosporinederivatives, such as midostaurin; examples of further compounds includeUCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO318220 and RO 320432; GO 6976; lsis 3521; LY333531/LY379196;isochinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) orAT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibitingthe activity of protein-tyrosine kinase inhibitors, such as compoundswhich target, decrease or inhibit the activity of protein-tyrosinekinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostinsuch as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer;Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR₁ ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, C1-1033, EKB-569, GW-2016, E1.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib.

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof; see WO2008118802), navitoclax (and analogsthereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng PharmaceuticalUniversity), obatoclax (and analogs thereof, see WO2004106328), S-001(Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), andvenetoclax. In some embodiments the Bcl-2 inhibitor is a small moleculetherapeutic. In some embodiments the Bcl-2 inhibitor is apeptidomimetic.

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218, U.S. Pat. No. 7,514,444, WO2011090760, and U.S.Pat. No. 8,338,439, the entirety of each of which is herein incorporatedby reference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2003063794, U.S. Pat. No. 7,557,210, WO2005007623, U.S. Pat.No. 7,173,015, WO2006078846, and U.S. Pat. No. 7,449,458, the entiretyof each of which is herein incorporated by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, U.S. Pat. No. 7,713,943, WO2004089925, U.S. Pat.No. 6,949,537, WO2007016176, U.S. Pat. Nos. 7,402,325, 8,138,347,WO2002088112, U.S. Pat. No. 7,071,189, WO2007084786, U.S. Pat. No.8,217,035, WO2007129161, U.S. Pat. No. 7,781,433, WO2006122806, U.S.Pat. No. 7,667,039, WO2005113554, U.S. Pat. No. 7,932,260, WO2007044729,and U.S. Pat. No. 7,989,622, the entirety of each of which is hereinincorporated by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, U.S. Pat. No. 8,185,616, WO2008109943, U.S. Pat.No. 8,486,941, WO2007053452, U.S. Pat. No. 7,528,143, WO200142246, U.S.Pat. No. 6,627,754, WO2007070514, and U.S. Pat. No. 7,598,257, theentirety of each of which is herein incorporated by reference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777(Zarnestra™). The term “telomerase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of telomerase.Compounds which target, decrease or inhibit the activity of telomeraseare especially compounds which inhibit the telomerase receptor, such astelomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase, and Bcl-2 inhibitors.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®) PRO64553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412. In some embodiments, the presentinvention provides a method of treating AML associated with an ITDand/or D835Y mutation, comprising administering a compound of thepresent invention together with a one or more FLT3 inhibitors. In someembodiments, the FLT3 inhibitors are selected from quizartinib (AC220),a staurosporine derivative (e.g. midostaurin or lestaurtinib),sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302,NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028,fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3inhibitors are selected from quizartinib, midostaurin, lestaurtinib,sorafenib, and sunitinib.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl)2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or apharmaceutically acceptable salt thereof, especially the lactate salt.Somatostatin receptor antagonists as used herein refer to compoundswhich target, treat or inhibit the somatostatin receptor such asoctreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with other drug substances such asanti-inflammatory, bronchodilatory or antihistamine drug substances,particularly in the treatment of obstructive or inflammatory airwaysdiseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Acompound of the invention may be mixed with the other drug substance ina fixed pharmaceutical composition or it may be administered separately,before, simultaneously with or after the other drug substance.Accordingly the invention includes a combination of a compound of theinvention as hereinbefore described with an anti-inflammatory,bronchodilatory, antihistamine or anti-tussive drug substance, saidcompound of the invention and said drug substance being in the same ordifferent pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate; non-steroidalglucocorticoid receptor agonists; LTB4 antagonists such LY293111,CGS025019C, CP-195543, SC-53228, BILL 284, ONO 4057, SB 209247; LTD4antagonists such as montelukast and zafirlukast; PDE4 inhibitors suchcilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A(Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline(Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281(Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene),VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2aagonists; A2b antagonists; and beta-2 adrenoceptor agonists such asalbuterol (salbutamol), metaproterenol, terbutaline, salmeterolfenoterol, procaterol, and especially, formoterol and pharmaceuticallyacceptable salts thereof. Suitable bronchodilatory drugs includeanticholinergic or antimuscarinic compounds, in particular ipratropiumbromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), andglycopyrrolate.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine.

Other useful combinations of compounds of the invention withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, and Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770).

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of one or more other therapeutic agent present in thecompositions of this invention may be no more than the amount that wouldnormally be administered in a composition comprising that therapeuticagent as the only active agent. Preferably the amount of one or moreother therapeutic agent in the presently disclosed compositions willrange from about 50% to 100% of the amount normally present in acomposition comprising that agent as the only therapeutically activeagent. In some embodiments, one or more other therapeutic agent isadministered at a dosage of about 50%, about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% ofthe amount normally administered for that agent. As used herein, thephrase “normally administered” means the amount an FDA approvedtherapeutic agent is approvided for dosing per the FDA label insert.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

Exemplary Immuno-Oncology Agents

In some embodiments, one or more other therapeutic agent is animmuno-oncology agent. As used herein, the term “an immuno-oncologyagent” refers to an agent which is effective to enhance, stimulate,and/or up-regulate immune responses in a subject. In some embodiments,the administration of an immuno-oncology agent with a compound of theinvention has a synergic effect in treating a cancer.

An immuno-oncology agent can be, for example, a small molecule drug, anantibody, or a biologic or small molecule. Examples of biologicimmuno-oncology agents include, but are not limited to, cancer vaccines,antibodies, and cytokines. In some embodiments, an antibody is amonoclonal antibody. In some embodiments, a monoclonal antibody ishumanized or human.

In some embodiments, an immuno-oncology agent is (i) an agonist of astimulatory (including a co-stimulatory) receptor or (ii) an antagonistof an inhibitory (including a co-inhibitory) signal on T cells, both ofwhich result in amplifying antigen-specific T cell responses.

Certain of the stimulatory and inhibitory molecules are members of theimmunoglobulin super family (IgSF). One important family ofmembrane-bound ligands that bind to co-stimulatory or co-inhibitoryreceptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1),B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.Another family of membrane bound ligands that bind to co-stimulatory orco-inhibitory receptors is the TNF family of molecules that bind tocognate TNF receptor family members, which includes CD40 and CD40L,OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB),TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK,RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR,LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,Lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, Lymphotoxin α1β2, FAS, FASL,RELT, DR6, TROY, NGFR.

In some embodiments, an immuno-oncology agent is a cytokine thatinhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and otherimmunosuppressive cytokines) or a cytokine that stimulates T cellactivation, for stimulating an immune response.

In some embodiments, a combination of a compound of the invention and animmuno-oncology agent can stimulate T cell responses. In someembodiments, an immuno-oncology agent is: (i) an antagonist of a proteinthat inhibits T cell activation (e.g., immune checkpoint inhibitors)such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1,BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP,PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein thatstimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137),4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3and CD28H.

In some embodiments, an immuno-oncology agent is an antagonist ofinhibitory receptors on NK cells or an agonists of activating receptorson NK cells. In some embodiments, an immuno-oncology agent is anantagonists of KIR, such as lirilumab.

In some embodiments, an immuno-oncology agent is an agent that inhibitsor depletes macrophages or monocytes, including but not limited toCSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155(WO 2011/070024, US 2011/0165156, WO 2011/0107553, US 2012/0329997, WO2011/131407, US 2013/0005949, WO 2013/087699, US 2014/0336363, WO2013/119716, WO 2013/132044, US 2014/0079706) or FPA-008 (WO2011/140249, US 2011/0274683; WO 2013/169264; WO 2014/036357, US2014/0079699).

In some embodiments, an immuno-oncology agent is selected from agonisticagents that ligate positive costimulatory receptors, blocking agentsthat attenuate signaling through inhibitory receptors, antagonists, andone or more agents that increase systemically the frequency ofanti-tumor T cells, agents that overcome distinct immune suppressivepathways within the tumor microenvironment (e.g., block inhibitoryreceptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibitTregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab)or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes suchas IDO, or reverse/prevent T cell energy or exhaustion) and agents thattrigger innate immune activation and/or inflammation at tumor sites.

In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. Insome embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4antibody. In some embodiments, an antagonistic CTLA-4 antibody is YERVOY(ipilimumab) or tremelimumab.

In some embodiments, an immuno-oncology agent is a PD-1 antagonist. Insome embodiments, a PD-1 antagonist is administered by infusion. In someembodiments, an immuno-oncology agent is an antibody or anantigen-binding portion thereof that binds specifically to a ProgrammedDeath-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments,a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments,an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA(pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In someembodiments, an immuno-oncology agent may be pidilizumab (CT-011). Insome embodiments, an immuno-oncology agent is a recombinant proteincomposed of the extracellular domain of PD-L2 (B7-DC) fused to the Fcportion of IgG1, called AMP-224.

In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. Insome embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody.In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634, US 2010/0203056), durvalumab (MEDI4736), BMS-936559 (WO2007/005874, US 2009/0055944), and MSB0010718C (WO 2013/079174, US2014/0341917).

In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. Insome embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody.In some embodiments, a LAG3 antibody is BMS-986016 (WO 2010/019570, US2010/0150892, WO 2014/008218, US 2014/0093511), or IMP-731 or IMP-321(WO 2008/132601, US 2010/0233183, WO 2009/044273, US 2011/0008331).

In some embodiments, an immuno-oncology agent is a CD137 (4-1BB)agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonisticCD137 antibody. In some embodiments, a CD137 antibody is urelumab orPF-05082566 (WO12/32433).

In some embodiments, an immuno-oncology agent is a GITR agonist. In someembodiments, a GITR agonist is an agonistic GITR antibody. In someembodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO2006/105021, US 2007/0098719, WO 2009/009116, US 2009/0136494), orMK-4166 (WO 2011/028683, US 2012/0189639).

In some embodiments, an immuno-oncology agent is an indoleamine(2,3)-dioxygenase (IDO) antagonist. In some embodiments, an IDOantagonist is selected from epacadostat (INCB024360, Incyte); indoximod(NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis);GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287(Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme thatbreaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919 (WO2009/073620, US 2011/0053941, WO 2009/132238, US 2011/0136796, WO2011/056652, US 2012/0277217, WO 2012/142237, US 2014/0066625).

In some embodiments, an immuno-oncology agent is an OX40 agonist. Insome embodiments, an OX40 agonist is an agonistic OX40 antibody. In someembodiments, an OX40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, an immuno-oncology agent is an OX40L antagonist. Insome embodiments, an OX40L antagonist is an antagonistic OX40 antibody.In some embodiments, an OX40L antagonist is RG-7888 (WO 2006/029879,U.S. Pat. No. 7,501,496).

In some embodiments, an immuno-oncology agent is a CD40 agonist. In someembodiments, a CD40 agonist is an agonistic CD40 antibody. In someembodiments, an immuno-oncology agent is a CD40 antagonist. In someembodiments, a CD40 antagonist is an antagonistic CD40 antibody. In someembodiments, a CD40 antibody is lucatumumab or dacetuzumab.

In some embodiments, an immuno-oncology agent is a CD27 agonist. In someembodiments, a CD27 agonist is an agonistic CD27 antibody. In someembodiments, a CD27 antibody is varlilumab.

In some embodiments, an immuno-oncology agent is MGA271 (to B7H3) (WO2011/109400, US 2013/0149236).

In some embodiments, an immuno-oncology agent is abagovomab,adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab,atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab,epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab,ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab,obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab,pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

In some embodiments, an immuno-oncology agent is an immunostimulatoryagent. For example, antibodies blocking the PD-1 and PD-L1 inhibitoryaxis can unleash activated tumor-reactive T cells and have been shown inclinical trials to induce durable anti-tumor responses in increasingnumbers of tumor histologies, including some tumor types thatconventionally have not been considered immunotherapy sensitive. See,e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al.(2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®,Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558),has shown potential to improve the overall survival in patients with RCCwho had experienced disease progression during or after prioranti-angiogenic therapy.

In some embodiments, the immunomodulatory therapeutic specificallyinduces apoptosis of tumor cells. Approved immunomodulatory therapeuticswhich may be used in the present invention include pomalidomide(Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenolmebutate (Picato®, LEO Pharma).

In some embodiments, an immuno-oncology agent is a cancer vaccine. Insome embodiments, the cancer vaccine is selected from sipuleucel-T(Provenge®, Dendreon/Valeant Pharmaceuticals), which has been approvedfor treatment of asymptomatic, or minimally symptomatic metastaticcastrate-resistant (hormone-refractory) prostate cancer; and talimogenelaherparepvec (Imlygic®, BioVex/Amgen, previously known as T-VEC), agenetically modified oncolytic viral therapy approved for treatment ofunresectable cutaneous, subcutaneous and nodal lesions in melanoma. Insome embodiments, an immuno-oncology agent is selected from an oncolyticviral therapy such as pexastimogene devacirepvec (PexaVec/JX-594,SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-)deficient vaccinia virus engineered to express GM-CSF, forhepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312);pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratoryenteric orphan virus (reovirus) which does not replicate in cells thatare not RAS-activated, in numerous cancers, including colorectal cancer(NCT01622543); prostate cancer (NCT01619813); head and neck squamouscell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); andnon-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev(NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineeredto express a full length CD80 and an antibody fragment specific for theT-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastaticor advanced epithelial tumors such as in colorectal cancer, bladdercancer, head and neck squamous cell carcinoma and salivary gland cancer(NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirusengineered to express GM-CSF, in melanoma (NCT03003676); and peritonealdisease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1(GLV-1h68/GLV-1h153, Genelux GmbH), vaccinia viruses engineered toexpress beta-galactosidase (beta-gal)/beta-glucoronidase orbeta-gal/human sodium iodide symporter (hNIS), respectively, werestudied in peritoneal carcinomatosis (NCT01443260); fallopian tubecancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), anadenovirus engineered to express GM-CSF, in bladder cancer(NCT02365818).

In some embodiments, an immuno-oncology agent is selected from JX-929(SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growthfactor-deficient vaccinia virus engineered to express cytosinedeaminase, which is able to convert the prodrug 5-fluorocytosine to thecytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos),peptide-based immunotherapy agents targeted for difficult-to-treat RASmutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirusdesignated: Ad5/3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP(ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered toexpress the glycoprotein (GP) of lymphocytic choriomeningitis virus(LCMV), which can be further engineered to express antigens designed toraise an antigen-specific CD8⁺ T cell response.

In some embodiments, an immuno-oncology agent is a T-cell engineered toexpress a chimeric antigen receptor, or CAR. The T-cells engineered toexpress such chimeric antigen receptor are referred to as a CAR-T cells.

CARs have been constructed that consist of binding domains, which may bederived from natural ligands, single chain variable fragments (scFv)derived from monoclonal antibodies specific for cell-surface antigens,fused to endodomains that are the functional end of the T-cell receptor(TCR), such as the CD3-zeta signaling domain from TCRs, which is capableof generating an activation signal in T lymphocytes. Upon antigenbinding, such CARs link to endogenous signaling pathways in the effectorcell and generate activating signals similar to those initiated by theTCR complex.

For example, in some embodiments the CAR-T cell is one of thosedescribed in U.S. Pat. No. 8,906,682, the entirety of each of which isherein incorporated by reference, which discloses CAR-T cells engineeredto comprise an extracellular domain having an antigen binding domain(such as a domain that binds to CD19), fused to an intracellularsignaling domain of the T cell antigen receptor complex zeta chain (suchas CD3 zeta). When expressed in the T cell, the CAR is able to redirectantigen recognition based on the antigen binding specificity. In thecase of CD19, the antigen is expressed on malignant B cells. Over 200clinical trials are currently in progress employing CAR-T in a widerange of indications.[https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

In some embodiments, an immunostimulatory agent is an activator ofretinoic acid receptor-related orphan receptor γ (RORγt). RORγt is atranscription factor with key roles in the differentiation andmaintenance of Type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) Tcells, as well as the differentiation of IL-17 expressing innate immunecell subpopulations such as NK cells. In some embodiments, an activatorof RORγt is LYC-55716 (Lycera), which is currently being evaluated inclinical trials for the treatment of solid tumors (NCT02929862).

In some embodiments, an immunostimulatory agent is an agonist oractivator of a toll-like receptor (TLR). Suitable activators of TLRsinclude an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101is an immunostimulatory CpG which is being studied for B-cell,follicular and other lymphomas (NCT02254772). Agonists or activators ofTLR8 which may be used in the present invention include motolimod(VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamouscell cancer of the head and neck (NCT02124850) and ovarian cancer(NCT02431559).

Other immuno-oncology agents that may be used in the present inventioninclude urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), ananti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), ananti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, InnatePharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody;monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2Amonoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), ananti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonalantibody.

In some embodiments, an immunostimulatory agent is selected fromelotuzumab, mifamurtide, an agonist or activator of a toll-likereceptor, and an activator of RORγt.

In some embodiments, an immunostimulatory therapeutic is recombinanthuman interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic asa therapy for melanoma and renal cell carcinoma (NCT01021059 andNCT01369888) and leukemias (NCT02689453). In some embodiments, animmunostimulatory agent is recombinant human interleukin 12 (rhIL-12).In some embodiments, an IL-15 based immunotherapeutic is heterodimericIL-15 (hetIL-15, Novartis/Admune), a fusion complex composed of asynthetic form of endogenous IL-15 complexed to the soluble IL-15binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which hasbeen tested in Phase 1 clinical trials for melanoma, renal cellcarcinoma, non-small cell lung cancer and head and neck squamous cellcarcinoma (NCT02452268). In some embodiments, a recombinant humaninterleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724,or NCT02542124.

In some embodiments, an immuno-oncology agent is selected from thosedescripted in Jerry L. Adams ET. AL., “Big opportunities for smallmolecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages603-622, the content of which is incorporated herein by reference in itsentirety. In some embodiments, an immuno-oncology agent is selected fromthe examples described in Table 1 of Jerry L. Adams ET. AL. In someembodiments, an immuno-oncology agent is a small molecule targeting animmuno-oncology target selected from those listed in Table 2 of Jerry L.Adams ET. AL. In some embodiments, an immuno-oncology agent is a smallmolecule agent selected from those listed in Table 2 of Jerry L. AdamsET. AL.

In some embodiments, an immuno-oncology agent is selected from the smallmolecule immuno-oncology agents described in Peter L. Toogood, “Smallmolecule immuno-oncology therapeutic agents,” Bioorganic & MedicinalChemistry Letters 2018, Vol. 28, pages 319-329, the content of which isincorporated herein by reference in its entirety. In some embodiments,an immuno-oncology agent is an agent targeting the pathways as describedin Peter L. Toogood.

In some embodiments, an immuno-oncology agent is selected from thosedescribed in Sandra L. Ross et al., “Bispecific T cell engager (BiTE®)antibody constructs can mediate bystander tumor cell killing”, PLoS ONE12(8): e0183390, the content of which is incorporated herein byreference in its entirety. In some embodiments, an immuno-oncology agentis a bispecific T cell engager (BiTE®) antibody construct. In someembodiments, a bispecific T cell engager (BiTE®) antibody construct is aCD19/CD3 bispecific antibody construct. In some embodiments, abispecific T cell engager (BiTE®) antibody construct is an EGFR/CD3bispecific antibody construct. In some embodiments, a bispecific T cellengager (BiTE®) antibody construct activates T cells. In someembodiments, a bispecific T cell engager (BiTE®) antibody constructactivates T cells, which release cytokines inducing upregulation ofintercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells.In some embodiments, a bispecific T cell engager (BiTE®) antibodyconstruct activates T cells which result in induced bystander celllysis. In some embodiments, the bystander cells are in solid tumors. Insome embodiments, the bystander cells being lysed are in proximity tothe BiTE®-activated T cells. In some embodiment, the bystander cellscomprises tumor-associated antigen (TAA) negative cancer cells. In someembodiment, the bystander cells comprise EGFR-negative cancer cells. Insome embodiments, an immuno-oncology agent is an antibody which blocksthe PD-L1/PD1 axis and/or CTLA4. In some embodiments, an immuno-oncologyagent is an ex-vivo expanded tumor-infiltrating T cell. In someembodiments, an immuno-oncology agent is a bispecific antibody constructor chimeric antigen receptors (CARs) that directly connect T cells withtumor-associated surface antigens (TAAs).

Exemplary Immune Checkpoint Inhibitors

In some embodiments, an immuno-oncology agent is an immune checkpointinhibitor as described herein.

The term “checkpoint inhibitor” as used herein relates to agents usefulin preventing cancer cells from avoiding the immune system of thepatient. One of the major mechanisms of anti-tumor immunity subversionis known as “T-cell exhaustion,” which results from chronic exposure toantigens that has led to up-regulation of inhibitory receptors. Theseinhibitory receptors serve as immune checkpoints in order to preventuncontrolled immune reactions.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cellImmunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3(Lag-3; CD223), and others are often referred to as a checkpointregulators. They act as molecular “gatekeepers” that allow extracellularinformation to dictate whether cell cycle progression and otherintracellular signaling processes should proceed.

In some embodiments, an immune checkpoint inhibitor is an antibody toPD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) toprevent the receptor from binding to the inhibitory ligand PDL-1, thusoverriding the ability of tumors to suppress the host anti-tumor immuneresponse.

In one aspect, the checkpoint inhibitor is a biologic therapeutic or asmall molecule. In another aspect, the checkpoint inhibitor is amonoclonal antibody, a humanized antibody, a fully human antibody, afusion protein or a combination thereof. In a further aspect, thecheckpoint inhibitor inhibits a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GALS, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an additional aspect, the checkpoint inhibitorinteracts with a ligand of a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an aspect, the checkpoint inhibitor is animmunostimulatory agent, a T cell growth factor, an interleukin, anantibody, a vaccine or a combination thereof. In a further aspect, theinterleukin is IL-7 or IL-15. In a specific aspect, the interleukin isglycosylated IL-7. In an additional aspect, the vaccine is a dendriticcell (DC) vaccine.

Checkpoint inhibitors include any agent that blocks or inhibits in astatistically significant manner, the inhibitory pathways of the immunesystem. Such inhibitors may include small molecule inhibitors or mayinclude antibodies, or antigen binding fragments thereof, that bind toand block or inhibit immune checkpoint receptors or antibodies that bindto and block or inhibit immune checkpoint receptor ligands. Illustrativecheckpoint molecules that may be targeted for blocking or inhibitioninclude, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4,BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 familyof molecules and is expressed on all NK, γδ, and memory CD8⁺ (αβ) Tcells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2kinases, A2aR, and various B-7 family ligands. B7 family ligandsinclude, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3,B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies,or antigen binding fragments thereof, other binding proteins, biologictherapeutics, or small molecules, that bind to and block or inhibit theactivity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3,GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immunecheckpoint inhibitors include Tremelimumab (CTLA-4 blocking antibody),anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-H1; MEDI4736), MK-3475(PD-1 blocker), Nivolumab (anti-PD1 antibody), CT-011 (anti-PD1antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody),BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody),MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpointinhibitor). Checkpoint protein ligands include, but are not limited toPD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

In certain embodiments, the immune checkpoint inhibitor is selected froma PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In someembodiments, the checkpoint inhibitor is selected from the groupconsisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), andpembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitoris selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-MyersSquibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck);ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb);durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); andatezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

In some embodiments, the checkpoint inhibitor is selected from the groupconsisting of lambrolizumab (MK-3475), nivolumab (BMS-936558),pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A,BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®),and tremelimumab.

In some embodiments, an immune checkpoint inhibitor is REGN2810(Regeneron), an anti-PD-1 antibody tested in patients with basal cellcarcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cellcarcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma(NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibodythat binds to PD-1, in clinical trials for diffuse large B-cell lymphomaand multiple myeloma; avelumab (Bavencio®, Pfizer/Merck KGaA), alsoknown as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, inclinical trials for non-small cell lung cancer, Merkel cell carcinoma,mesothelioma, solid tumors, renal cancer, ovarian cancer, bladdercancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis),an inhibitory antibody that binds to PD-1, in clinical trials fornon-small cell lung cancer, melanoma, triple negative breast cancer andadvanced or metastatic solid tumors. Tremelimumab (CP-675,206;Astrazeneca) is a fully human monoclonal antibody against CTLA-4 thathas been in studied in clinical trials for a number of indications,including: mesothelioma, colorectal cancer, kidney cancer, breastcancer, lung cancer and non-small cell lung cancer, pancreatic ductaladenocarcinoma, pancreatic cancer, germ cell cancer, squamous cellcancer of the head and neck, hepatocellular carcinoma, prostate cancer,endometrial cancer, metastatic cancer in the liver, liver cancer, largeB-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplasticthyroid cancer, urothelial cancer, fallopian tube cancer, multiplemyeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884(Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1clinical trials for advanced solid tumors (NCT02694822).

In some embodiments, a checkpoint inhibitor is an inhibitor of T-cellimmunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors thatmay be used in the present invention include TSR-022, LY3321367 andMBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is beingstudied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is ananti-TIM-3 antibody which is being studied in solid tumors(NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which isbeing studied in advanced malignancies (NCT02608268).

In some embodiments, a checkpoint inhibitor is an inhibitor of T cellimmunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor oncertain T cells and NK cells. TIGIT inhibitors that may be used in thepresent invention include BMS-986207 (Bristol-Myers Squibb), ananti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); andanti-TIGIT monoclonal antibody (NCT03119428).

In some embodiments, a checkpoint inhibitor is an inhibitor ofLymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be usedin the present invention include BMS-986016 and REGN3767 and IMP321.BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is beingstudied in glioblastoma and gliosarcoma (NCT02658981). REGN3767(Regeneron), is also an anti-LAG-3 antibody, and is being studied inmalignancies (NCT03005782). IMP321 (Immutep S.A.) is an LAG-3-Ig fusionprotein, being studied in melanoma (NCT02676869); adenocarcinoma(NCT02614833); and metastatic breast cancer (NCT00349934).

Checkpoint inhibitors that may be used in the present invention includeOX40 agonists. OX40 agonists that are being studied in clinical trialsinclude PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody,in metastatic kidney cancer (NCT03092856) and advanced cancers andneoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonisticanti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562(Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advancedsolid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonisticanti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectalcancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer(NCT02274155) and metastatic prostate cancer (NCT01303705); andBMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, inadvanced cancers (NCT02737475).

Checkpoint inhibitors that may be used in the present invention includeCD137 (also called 4-1BB) agonists. CD137 agonists that are beingstudied in clinical trials include utomilumab (PF-05082566, Pfizer) anagonistic anti-CD137 antibody, in diffuse large B-cell lymphoma(NCT02951156) and in advanced cancers and neoplasms (NCT02554812 andNCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonisticanti-CD137 antibody, in melanoma and skin cancer (NCT02652455) andglioblastoma and gliosarcoma (NCT02658981).

Checkpoint inhibitors that may be used in the present invention includeCD27 agonists. CD27 agonists that are being studied in clinical trialsinclude varlilumab (CDX-1127, Celldex Therapeutics) an agonisticanti-CD27 antibody, in squamous cell head and neck cancer, ovariancarcinoma, colorectal cancer, renal cell cancer, and glioblastoma(NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma(NCT02924038).

Checkpoint inhibitors that may be used in the present invention includeglucocorticoid-induced tumor necrosis factor receptor (GITR) agonists.GITR agonists that are being studied in clinical trials include TRX518(Leap Therapeutics), an agonistic anti-GITR antibody, in malignantmelanoma and other malignant solid tumors (NCT01239134 and NCT02628574);GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors andlymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonisticanti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110);MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors(NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistichexameric GITR-ligand molecule with a human IgG1 Fc domain, in advancedsolid tumors (NCT02583165).

Checkpoint inhibitors that may be used in the present invention includeinducible T-cell co-stimulator (ICOS, also known as CD278) agonists.ICOS agonists that are being studied in clinical trials include MEDI-570(Medimmune), an agonistic anti-ICOS antibody, in lymphomas(NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, inPhase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonisticanti-ICOS antibody, in Phase 1 (NCT02904226).

Checkpoint inhibitors that may be used in the present invention includekiller IgG-like receptor (KIR) inhibitors. KIR inhibitors that are beingstudied in clinical trials include lirilumab (IPH2102/BMS-986015, InnatePharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias(NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma(NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, InnatePharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (InnatePharma), an anti-KIR antibody that binds to three domains of the longcytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

Checkpoint inhibitors that may be used in the present invention includeCD47 inhibitors of interaction between CD47 and signal regulatoryprotein alpha (SIRPa). CD47/SIRPa inhibitors that are being studied inclinical trials include ALX-148 (Alexo Therapeutics), an antagonisticvariant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediatedsignaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, TrilliumTherapeutics), a soluble recombinant fusion protein created by linkingthe N-terminal CD47-binding domain of SIRPa with the Fc domain of humanIgG1, acts by binding human CD47, and preventing it from delivering its“do not eat” signal to macrophages, is in clinical trials in Phase 1(NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.),in colorectal neoplasms and solid tumors (NCT02953782), acute myeloidleukemia (NCT02678338) and lymphoma (NCT02953509).

Checkpoint inhibitors that may be used in the present invention includeCD73 inhibitors. CD73 inhibitors that are being studied in clinicaltrials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solidtumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), ananti-CD73 antibody, in solid tumors (NCT02754141).

Checkpoint inhibitors that may be used in the present invention includeagonists of stimulator of interferon genes protein (STING, also known astransmembrane protein 173, or TMEM173). Agonists of STING that are beingstudied in clinical trials include MK-1454 (Merck), an agonisticsynthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100(MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclicdinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

Checkpoint inhibitors that may be used in the present invention includeCSF1R inhibitors. CSF1R inhibitors that are being studied in clinicaltrials include pexidartinib (PLX3397, Plexxikon), a CSF1R small moleculeinhibitor, in colorectal cancer, pancreatic cancer, metastatic andadvanced cancers (NCT02777710) and melanoma, non-small cell lung cancer,squamous cell head and neck cancer, gastrointestinal stromal tumor(GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly),an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma(NCT03101254), and solid tumors (NCT02718911); and BLZ945(4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide,Novartis), an orally available inhibitor of CSF1R, in advanced solidtumors (NCT02829723).

Checkpoint inhibitors that may be used in the present invention includeNKG2A receptor inhibitors. NKG2A receptor inhibitors that are beingstudied in clinical trials include monalizumab (IPH2201, Innate Pharma),an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) andchronic lymphocytic leukemia (NCT02557516).

In some embodiments, the immune checkpoint inhibitor is selected fromnivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab,atezolizumab, or pidilizumab.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Abbreviations

Ac: acetyl

AcOH: acetic acid

ACN: acetonitrile

Ad: adamantly

AIBN: 2,2′-azo bisisobutyronitrile

Anhyd: anhydrous

Aq: aqueous

B₂Pin₂: bis(pinacolato)diboron-4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)

BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

BH₃: Borane

Bn: benzyl

Boc: tert-butoxycarbonyl

Boc₂O: di-tert-butyl dicarbonate

BPO: benzoyl peroxide

^(n)BuOH: n-butanol

CDI: carbonyldiimidazole

COD: cyclooctadiene

d: days

DABCO: 1,4-diazobicyclo[2.2.2]octane

DAST: diethylaminosulfur trifluoride

dba: dibenzylideneacetone

DBU: 1,8-diazobicyclo[5.4.0]undec-7-ene

DCE: 1,2-dichloroethane

DCM: dichloromethane

DEA: diethylamine

DHP: dihydropyran

DIBAL-H: diisobutylaluminum hydride

DIPA: diisopropylamine

DIPEA or DIEA: N,N-diisopropylethylamine

DMA: N,N-dimethylacetamide

DME: 1,2-dimethoxyethane

DMAP: 4-dimethylaminopyridine

DMF: N,N-dimethylformamide

DMP: Dess-Martin periodinane

DMSO-dimethyl sulfoxide

DPPA: diphenylphosphoryl azide

dppf: 1,1′-bis(diphenylphosphino)ferrocene

EDC or EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

ee: enantiomeric excess

ESI: electrospray ionization

EA: ethyl acetate

EtOAc: ethyl acetate

EtOH: ethanol

FA: formic acid

h or hrs: hours

HATU: N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate

HCl: hydrochloric acid

HPLC: high performance liquid chromatography

HOAc: acetic acid

IBX: 2-iodoxybenzoic acid

IPA: isopropyl alcohol

KHMDS: potassium hexamethyldisilazide

K₂CO₃: potassium carbonate

LAH: lithium aluminum hydride

LDA: lithium diisopropylamide

m-CPBA: meta-chloroperbenzoic acid

M: molar

MeCN: acetonitrile

MeOH: methanol

Me₂S: dimethyl sulfide

MeONa: sodium methylate

Met iodomethane

min: minutes

mL: milliliters

mM: millimolar

mmol: millimoles

MPa: mega pascal

MOMCl: methyl chloromethyl ether

MsCl: methanesulfonyl chloride

MTBE: methyl tert-butyl ether

nBuLi: n-butyllithium

NaNO₂: sodium nitrite

NaOH: sodium hydroxide

Na₂SO₄: sodium sulfate

NBS: N-bromosuccinimide

NCS: N-chlorosuccinimide

NFSI: N-Fluorobenzenesulfonimide

NMO: N-methylmorpholine N-oxide

NMP: N-methylpyrrolidine

NMR: Nuclear Magnetic Resonance

° C.: degrees Celsius

Pd/C: Palladium on Carbon

Pd(OAc)₂: Palladium Acetate

PBS: phosphate buffered saline

PE: petroleum ether

POCl₃: phosphorus oxychloride

PPh₃: triphenylphosphine

PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate

Rel: relative

R.T. or rt: room temperature

sat: saturated

SEMCl: chloromethyl-2-trimethylsilylethyl ether

SFC: supercritical fluid chromatography

SOCl₂: sulfur dichloride

tBuOK: potassium tert-butoxide

TBAB: tetrabutylammonium bromide

TBAI: tetrabutylammonium iodide

TEA: triethylamine

Tf: trifluoromethanesulfonate

TfAA, TFMSA or Tf₂O: trifluoromethanesulfonic anhydride

TFA: trifluoracetic acid

TIPS: triisopropylsilyl

THF: tetrahydrofuran

THP: tetrahydropyran

TLC: thin layer chromatography

TMEDA: tetramethylethylenediamine

pTSA: para-toluenesulfonic acid

wt: weight

Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

General Synthetic Methods

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

All reactions are carried out under nitrogen or argon unless otherwisestated.

Proton NMR NMR) is conducted in deuterated solvent. In certain compoundsdisclosed herein, one or more ¹H shifts overlap with residual proteosolvent signals; these signals have not been reported in theexperimental provided hereinafter.

TABLE 3 Analytical instruments LCMS Shimadzu UFLC MS: LCMS-2020 AgilentTechnologies 1200 series MS: Agilent Technologies 6110 AgilentTechnologies 1200 series MS: LC/MSD VL NMR BRUKER AVANCE III/400;Frequency (MHz) 400.13; Nucleus: 1H; Number of Transients: 8 Prep-HPLCGilson GX-281 systems: instruments GX-A, GX-B, GX-C, GX-D, GX-E, GX-F,GX-G and GX-H GCMS SHIMADZU GCMS-QP2010 Ultra Analytical AgilentTechnologies 1290 Infinity cSFC Prep-cSFC Waters SFC Prep 80

For acidic LCMS data: LCMS was recorded on an Agilent 1200 Series LC/MSDor Shimadzu LCMS2020 equipped with electro-spray ionization andquadruple MS detector [ES+ve to give MH⁺] and equipped with ChromolithFlash RP-18e 25*2.0 mm, eluting with 0.0375 vol % TFA in water (solventA) and 0.01875 vol % TFA in acetonitrile (solvent B). Other LCMS wasrecorded on an Agilent 1290 Infinity RRLC attached with Agilent 6120Mass detector. The column used was BEH C18 50*2.1 mm, 1.7 micron. Columnflow was 0.55 ml/min and mobile phase were used (A) 2 mM AmmoniumAcetate in 0.1% Formic Acid in Water and (B) 0.1% Formic Acid inAcetonitrile.

For basic LCMS data: LCMS was recorded on an Agilent 1200 Series LC/MSDor Shimadzu LCMS 2020 equipped with electro-spray ionization andquadruple MS detector [ES+ve to give MH⁺] and equipped with Xbridge C18,2.1×50 mm columns packed with 5 mm C18-coated silica or Kinetex EVO C182.1×30 mm columns packed with 5 mm C18-coated silica, eluting with 0.05vol % NH₃.H₂O in water (solvent A) and acetonitrile (solvent B).

HPLC Analytical Method: HPLC was carried out on X Bridge C18 150*4.6 mm,5 micron. Column flow was 1.0 ml/min and mobile phase were used (A) 0.1%Ammonia in water and (B) 0.1% Ammonia in Acetonitrile.

Prep HPLC Analytical Method: The compound was purified on ShimadzuLC-20AP and UV detector. The column used was X-BRIDGE C18 (250*19)mm,5μ. Column flow was 16.0 ml/min. Mobile phase were used (A) 0.1% FormicAcid in Water and (B) Acetonitrile Basic method used (A) 5 mM ammoniumbicarbonate and 0.1% NH3 in Water and (B) Acetonitrile or (A) 0.1%Ammonium Hydroxide in Water and (B) Acetonitrile. The UV spectra wererecorded at 202 nm & 254 nm.

NMR Method: The 1H NMR spectra were recorded on a Bruker Ultra ShieldAdvance 400 MHz/5 mm Probe (BBFO). The chemical shifts are reported inpart-per-million.

Example 1. 3-(9H-Carhazol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(1)

Step 1. 3-(9H-Carbazol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

To a solution of 9H-carbazole (2.0 g, 12.0 mmol) in DMF (20 mL) wasadded t-BuOK (1.61 g, 14.4 mmol) at 0° C. The mixture was stirred at0-10° C. for 1 hour under N2. Then3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (5.59 g, 18.0 mmol) inDMF (30 mL) was added to the reaction mixture at 0-10° C. during 20minutes. After addition, the mixture was stirred at room temperature for17 hours under N₂. On completion, the reaction was quenched by water andextracted with EA. The combined organic layer was washed with water andbrine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by column chromatography to give the titledcompound (0.35 g, 7.4% yield) as a yellow solid. LC-MS (ESI⁺): m/z 399.3(M+H)⁺.

Step 2. 3-(9H-Carbazol-9-yl)piperidine-2,6-dione

To a solution of3-(9H-carbazol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (0.1 g,0.25 mmol) in CH₃CN (4 mL) was added Diammonium cerium(IV) nitrate (0.41g, 0.75 mmol) in water (1 mL) at 0° C. The reaction mixture was stirredat this temperature for 1 hour, then diluted with water. The mixture waspurified via reverse phase column chromatography (CH₃CN/H₂O=5%-80%) togive the titled compound (7.5 mg, 10.7%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 8.49 (dd, J=7.5, 1.3 Hz, 1H), 8.25 (d, J=7.5 Hz, 1H),8.11-8.01 (m, 1H), 7.88 (s, 1H), 7.57-7.40 (m, 3H), 7.34-7.29 (m, 2H),5.51 (m, 1H), 3.08-2.94 (m, 2H), 2.74-2.53 (m, 2H). LC-MS (ESI⁺): m/z279.2 (M+H)⁺.

Example 2. 3-(9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (2)

Step 1.1-(4-Methoxybenzyl)-3-(9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of 9H-pyrido[2,3-b]indole (2 g, 12 mmol) in DMF (30 mL)was added t-BuOK (1.34 g, 12 mmol) at 0° C. The mixture was stirred at0-10° C. for 2 hour under N2. Then a solution of3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (5.6 g, 18 mmol) in DMF(20 mL) was added to the reaction mixture at 0-10° C. during 30 minutes.The mixture was warmed to room temperature and stirred for 30 minutesunder N2. The reaction was quenched water (50 mL) and extracted with EA(3×50 mL). The combined organic layer was concentrated in vacuo. Theresidue was purified by column chromatography (PE/EA) to give the crudecompound mix with the 9H-pyrido[2,3-b]indole. Then the mixture waspurified with prep HPLC eluting with ACN/H₂O (0.1% HCOOH) to get thetitle compound (538 mg) as a white solid (yield: 11.2%). LC-MS (ESI⁺):m/z 400.1 (M+H)⁺.

Step 2. 3-(9H-Pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of1-(4-methoxybenzyl)-3-(9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(400 mg, 1 mmol) in toluene (10 ml) was added MsOH (1.8 g, 20 mmol). Themixture was warmed to 100° C. and stirred for 2 h. The reaction mixturewas cooled to room temperature and concentrated in vacuo. The residuewas poured into ice/water (50 mL), extracted with EA (3×50 mL). Thecombined organic layer was washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified with prepHPLC eluting with ACN/H₂O (0.1% HCOOH) to get the titled compound (120mg, 43% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 11.15 (s,1H), 8.53-8.62 (m, 1H), 8.43 (dd, J=4.88, 1.50 Hz, 1H), 8.24 (d, J=7.63Hz, 1H), 7.62 (d, J=7.88 Hz, 1H), 7.46-7.56 (m, 1H), 7.24-7.37 (m, 2H),6.05 (br. s., 1H), 2.93-3.21 (m, 2H), 2.63-2.77 (m, 1H), 2.07-2.18 (m,1H). LC-MS (ESI⁺): m/z 280.0 (M+H)⁺.

Example 3. 3-(6-Amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(5)

Step 1. 6-Nitro-9H-pyrido[2,3-b]indole

To a solution of 9H-pyrido[2,3-b]indole (504 mg, 3 mmol) in conc. H₂SO₄(5 ml) was added dropwise a solution of nitric acid (68%-70% solution inwater)(297 mg, 3.3 mol) in con. H₂SO₄ (5 ml) at −5° C.-0° C. over 20mins. After addition, the mixture was added into ice water, thenbasified by addition of saturated NaOH solution to PH>8. The mixture wasextracted with EtOAc (3*200 ml), the combined organic layers wereevaporated to give the title compound as a yellow solid (500 mg, 78.2%yield) that was used directly in the next step without furtherpurification. LC-MS (ESI⁺): m/z 214.2 (M+H)⁺.

Step 2. tert-Butyl 6-nitro-9H-pyrido[2,3-b]indole-9-carboxylate

To a solution of 6-nitro-9H-pyrido[2,3-b]indole (500 mg, 2.35 mmol) inDCM (10 ml) was added Boc₂O (767 mg, 3.52 mmol) and DMAP (57.2 mg, 0.468mmol). The mixture was stirred at room temperature overnight. Thereaction mixture was evaporated. The residue was purified by silica gelchromatography (PE:EA=3:1) to give the title compound as a white solid(385 mg, 52.1% yield). 1H NMR (400 MHz, CDCl₃) δ: 8.90 (d, J=2.13 Hz,1H), 8.75 (dd, J=4.82, 1.56 Hz, 1H), 8.35-8.47 (m, 3H), 7.44 (dd,J=7.75, 4.88 Hz, 1H), 1.80 (s, 9H).

Step 3. 6-Nitro-9H-pyrido[2,3-b]indole

To a solution of tert-butyl 6-nitro-9H-pyrido[2,3-b]indole-9-carboxylate(300 mg, 0.96 mmol) in DCM (6 ml) was added TFA (2 ml). The mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated. The residue was resolved in DCM (20 ml), washed withsaturated NaHCO₃ solution (2*20 ml), the organic phase was washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo to give thecrude titled compound (200 mg, 95.4% yield) as a yellow solid. LC-MS(ESI⁺): m/z 214.2 (M+H)⁺

Step 4.1-(4-Methoxybenzyl)-3-(6-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of 6-nitro-9H-pyrido[2,3-b]indole (210 mg, 1 mmol) in THF(10 mL) was added t-BuOK (168 mg, 1.5 mmol) at 0° C. The mixture wasstirred at 0-10° C. for 1 hour under N2. Then a solution of[1-[(4-methoxyphenyl) methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (457 mg, 1.2 mmol) in THF(10 mL) was added to the reaction mixture at 0-10° C. during 20 minutes.The mixture was stirred at 0-10° C. for 30 minutes under N2. Additionalsolution of [1-[(4-methoxyphenyl) methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (114 mg, 0.3 mmol) in THF(5 mL) was added to the reaction mixture at 0-10° C. dropwise. Themixture was stirred at 0-10° C. for another 30 minutes under N2. Oncompletion, the reaction was quenched water (40 mL) and extracted withEA (3×50 mL). The combined organic layer was concentrated in vacuo. Theresidue was purified by column chromatography to give the titledcompound (400 mg) as a yellow solid. LC-MS (ESI⁺): m/z 445 (M+H)t

Step 5. 3-(6-Nitro-9H-pyrido[2,3]indol-9-yl)piperidine-2, 6-dione

To a solution of1-(4-methoxybenzyl)-3-(6-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(400 mg, 0.90 mmol) in CH₃CN (10 ml) was added a solution of CAN (2.46g, 0.45 mmol) in water (3 ml) at 0° C. After addition, the mixture waswarmed to room temperature and stirred overnight. The reaction mixturewas poured into water (50 ml), extract with EtOAc (3*50 ml), thecombined organic layers were concentrated in vacuo. The residue wastriturated with DMF/EA and filtrated to give the titled compound (130mg, 44.4% yield) as a grey solid. LC-MS (ESI⁺): m/z 325.0 (M+H)⁺.

Step 6. 3-(6-Amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(V763-123), (5)

To a solution of3-(6-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (130 mg,0.401 mmol) in THF (5 ml) and EA (5 ml) was added palladium on activatedcarbon 10% Pd (50 mg) The mixture was stirred at room temperature underhydrogen overnight. The reaction mixture was filtered, the filtrate wasconcentrated under reduce pressure, the residue was triturated withDMF/EA and filtrated to give the title compound (55 mg, 46.4% yield) asa grey solid. LC-MS (ESI⁺): m/z 295.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6)δ: 11.08 (s, 1H), 8.26-8.39 (m, 2H), 7.24-7.36 (m, 2H), 7.14 (dd,J=7.63, 4.88 Hz, 1H), 6.85 (dd, J=8.63, 2.13 Hz, 1H), 5.90 (br. s., 1H),4.87 (br. s., 2H), 2.93-3.08 (m, 2H), 2.68 (d, J=12.26 Hz, 1H),2.01-2.11 (m, 1H).

Example 4.N-(9-(2,6-Dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)acetamide (8)

To a solution of3-(6-amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (40 mg crude,0.136 mmol, 5) in ACN (5 ml) was added acetic anhydride (5 drops) andDIPEA (10 drops). The mixture was stirred at room temperature for 2 h.The mixture was filtered, the filtrate cake was dissolved in DCM, washedwith 1M HCl (2*10 ml), the organic phase was concentrated and dried togive the titled compound (8 mg, 17.4% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ: 11.14 (s, 1H), 10.02 (s, 1H), 8.45-8.55 (m, 2H),8.35-8.45 (m, 1H), 7.46-7.61 (m, 2H), 7.25 (dd, J=7.69, 4.82 Hz, 1H),6.02 (br. s., 1H), 2.93-3.17 (m, 2H), 2.63-2.76 (m, 1H), 2.06-2.14 (m,4H). LC-MS (ESI⁺): m/z 337.0 (M+H)⁺.

Example 5.1-(9-(2,6-Dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)-3-ethylurea(9)

To a solution of3-(6-amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (25 mg, 0.085mmol, 5) in ACN (5 ml) was added ethyl isocyanate (3 drops) and DIPEA (6drops). The mixture was stirred at room temperature for 4 h. The mixturewas concentrated in vacuo and the residue was purified by prep HPLC togive the title compound (8 mg, 25.7% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ: 11.13 (s, 1H), 8.43-8.54 (m, 2H), 8.39 (dd,J=4.82, 1.44 Hz, 1H), 8.27 (d, J=1.88 Hz, 1H), 7.37-7.52 (m, 2H), 7.22(dd, J=7.63, 4.88 Hz, 1H), 6.12 (t, J=5.50 Hz, 1H), 5.99 (br. s., 1H),3.10-3.20 (m, 2H), 2.90-3.07 (m, 2H), 2.65-2.75 (m, 1H), 2.06-2.16 (m,1H), 1.03-1.13 (m, 3H). LC-MS (ESI⁺): m/z 366.3 (M+H)⁺.

Example 6. tert-butyl(2-(2-(2-((9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)amino)ethoxy)ethoxy)ethyl)carbamate(10)

Step 1: tert-butyl (2-(2-(2-oxoethoxy)ethoxy)ethyl)carbamate

To a mixture of tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate(2 g, 8.03 mmol) and dess-martin periodinane in dichloromethane (20 mL)was added AcOH (1 mL). The mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressureand purified by flash chromatography to give tert-butyl(2-(2-(2-oxoethoxy)ethoxy)ethyl)carbamate (300 mg, 15.2%) as a colorlessoil. LC/MS (ESI, m/z): [M+1]⁺=248.1.

Step 2: tert-butyl(2-(2-(2-((9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)amino)ethoxy)ethoxy)ethyl)carbamate(10)

To a mixture of 5 (200 mg, 0.68 mmol) and(2-(2-(2-oxoethoxy)ethoxy)ethyl)carbamate (176 mg, 0.714 mmol) in THF (5mL) was added AcOH (5 drops). The mixture was stirred at roomtemperature for 2 h. Then NaCNBH₃ (21.3 mg, 0.34 mmol) was added inportions. The reaction mixture was warmed to 40° C. and stirred for 2 h.The reaction mixture was poured into water and extract with EtOAc (3×20mL). The combined organic layers were concentrated under reducedpressure. The residue was purified via reverse phase columnchromatography (CH₃CN/H₂O=5%-80%) to give 10 (70 mg, 19.6%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (br. s., 1H), 8.42 (dd, J=7.6,1.5 Hz, 1H), 8.33 (dd, J=4.8, 1.5 Hz, 1H), 7.36-7.32 (m, 2H), 7.17-7.13(m, 1H), 6.92 (dd, J=8.8, 2.2 Hz, 1H), 6.79-6.76 (m, 1H), 5.91 (br. s.,1H), 5.30 (br. s., 1H), 3.66-3.62 (m, 2H), 3.60-3.50 (m, 4H), 3.41-3.29(m, 4H), 3.12-2.95 (m, 4H), 2.71-2.65 (m, 1H), 2.12-2.01 (m, 1H), 1.37(s, 9H); LC/MS (ESI, m/z): [M+1]⁺=526.55

Example 7. 3-(6-Bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

Step 1: 6-Bromo-9H-pyrido[2,3-b]indole

To a stirred solution of 9H-pyrido[2,3-b]indole (3 g, 17.9 mmol) in DCM(50 mL) was added dropwise of Br₂ (3.4 g, 21.4 mmol) at 0° C. To themixture was added aq. NaHCO₃(100 mL), extracted with EA (200 mL). Theorganic layer was washed with brine (50 mL), dried over Na₂SO₄,filtered, concentrated to give product 6-bromo-9H-pyrido[2,3-b]indole(2.7 g, 61% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.02(s, 1H), 8.60 (dd, J=1.2 Hz, J=7.6 Hz, 1H), 8.48-8.44 (m, 2H), 7.60-7.58(m, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.26 (dd, J=4.8 Hz, J=7.6 Hz, 1H).LC/MS (ESI, m/z): [M+1]⁺=247.8.

Step 2:3-(6-Bromo-9H-pyrido[2,3-b]indol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

To a stirred solution of Intermediate A (200 mg, 0.810 mmol) and18-crown-6 (43 mg, 0.162 mmol) in dry THF (10 mL) was added dropwiseNaHMDS (0.6 mL, 2 M in THF) at −30° C. under N2. The mixture was stirredfor 1 h at −30° C. under N2. Then to the mixture was added a solution of1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate(463 mg, 1.21 mmol) in THF (5 mL) dropwise at −30° C. under N2. Themixture was stirred at −30° C. for 2 h. The mixture was added to aq.NH₄C1 (20 mL), extracted with EA (50 mL). The organic layer was washedwith brine (30 mL), dried over Na₂SO₄, filtered, concentrated andpurified by column (PE/EA/DCM=10/1/1 to 3/1/1) to give product3-(6-bromo-9H-pyrido[2,3-b]indol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(220 mg, 57% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.41 (dd,J=1.6 Hz, J=4.8 Hz, 1H), 8.29 (dd, J=1.2 Hz, J=7.6 Hz, 1H), 8.20 (J=1.6Hz, 1H), 7.45 (dd, J=2.0 Hz, J=8.6 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H),7.24-7.21 (m, 1H), 6.84 (d, J=8.8 Hz, 3H), 5.90-5.87 (m, 1H), 5.01 (dd,J=13.6 Hz, J=20.4 Hz, 2H), 3.81 (s, 3H), 3.09-2.84 (m, 4H); LC/MS (ESI,m/z): [M+1]⁺=479.1.

Step 3: 3-(6-Bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (11)

A mixture of3-(6-bromo-9H-pyrido[2,3-b]indol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(1.3 g, 2.72 mmol), MsOH (10 mL) and toluene (20 mL) was heated to 110°C. and stirred for 3 h under N2. The mixture was concentrated to removetoluene. Then to the mixture was added EA (50 mL), washed with brine (50mL) to remove MsOH. The organic layer was dried over Na₂SO₄,concentrated with silica gel and purified by column (PE/EA=1/1) to giveproduct 11 (500 mg, 51% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.13 (br s, 1H), 8.64 (dd, J=1.6 Hz, J=7.6 Hz, 1H), 8.52 (d,J=2.0 Hz, 1H), 8.47 (dd, J=1.6 Hz, J=4.8 Hz, 1H), 7.68-7.62 (m, 2H),7.31 (dd, J=4.8 Hz, J=7.6 Hz, 1H), 6.06 (s, 1H), 3.16-2.96 (m, 2H),2.73-2.67 (m, 1H), 2.16-2.13 (m, 1H). LC/MS (ESI, m/z):[M+1]⁺=358.0/360.0.

Example 8. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) Assay

Equal volumes of His-tagged CRBN-DDB1 complex (56 nM) was mixed withEu-cryptate labeled Anti-6HIS-monoclonal antibody (50x dilution from thecommercial stock solution, Vender: Cisbio, Cat. #61HI2KLA) in a finalbuffer containing 20 mM HEPES pH 7.0, 150 mM NaCl, 0.005% Tween-20. Thesolution was then mixed with Cy5-labeled thalidomide (final 8 nM) andvarious concentrations of compounds (a serial 3-fold dilution with thetop concentration 200 uM). The mixture were incubated at roomtemperature for 1 hour. FRET signals were measured on an EnVision platereader (Perkin Elmer) by exciting at 340 nm and recording emission atboth 615 nm as no FRET control and 665 nm as the FRET signals with a 60microsecond delay. FRET efficiency was calculated as the ratio offluorescent signals at 665 nM/615 nM. Quantitative loss of FRETefficiency as a function of compound concentrations was fitted by afour-parameter Logistic Function using GraphPad Prism 7.0 and the IC50values were reported for each compound.

Table 4 shows the results for selected compounds in the time-resolvedfluorescence resonance energy transfer (TR-FRET) assay. The compoundnumbers correspond to the compound numbers in the Examples. Compoundshaving an activity designated as “A” provided an IC₅₀ of <10 μM;compounds having an activity designated as “B” provided an IC₅₀ of 10-30μM; compounds having an activity designated as “C” provided an IC₅₀ of30-100 μM; and compounds having an activity designated as “D” providedan IC₅₀ of >100 μM. For reference, the known CRBN binders provided thefollowing IC₅₀ values in the TR-FRET assay: thalidomide (IC₅₀=2.9 μM),lenalidomide (IC₅₀=1.17 μM) and pomalidomide (IC₅₀=1.28 μM).

TABLE 4 TR-FRET Assay Results CMPD # CRBN HTRF IC₅₀ (μM) 2 A 5 A 8 A 9 A10 A 11 A

Example 9. General Method A. Synthesis of3-[6-[7-[2-[3-[3-amino-6-(2-hydroxyphenyl) pyridazin-4-yl]-3,8-diazabicyclo [3.2.1] octan-8-yl] pyrimidin-5-yl] heptyl] pyrido [2,3-b] indol-9-yl] piperidine-2, 6-dione (I-107)

Step 1:3-[6-[7-[2-[3-[3-amino-6-(2-benzyloxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyrimidin-5-yl]hepta-1,6-diynyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione

A mixture of6-(2-benzyloxyphenyl)-4-[8-(5-hepta-1,6-diynylpyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-amine(150 mg, 269 umol),3-(6-bromopyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (96.6 mg, 269umol, 11), CuI (10.2 mg, 53.9 umol), CsF (164 mg, 1.08 mmol),Pd(PPh₃)₂Cl₂ (18.9 mg, 26.9 umol) and 4 A molecular sieve (150 mg, 55.8umol) in DMSO (6 mL) was degassed and purged with N2 for 3 times, andthen the mixture was stirred at 85° C. for 12 hrs under N2 atmosphere.The reaction mixture was diluted with brine 30 mL and extracted with EA(30 mL*3). The combined organic layers were washed with brine (30 mL*3),dried over sodium sulfate, filtered and concentrated under reducedpressure to give a residue. The residue was purified by reversed phaseflash (FA condition; 45% MeCN to 55% MeCN) to give the title compound(60 mg, 23% yield) as a white solid. LC-MS (ESI+) m/z 833.5 (M+H)⁺.

Step 2:3-[6-[7-[2-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyrimidin-5-yl]heptyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione

To a solution of3-[6-[7-[2-[3-[3-amino-6-(2-benzyloxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyrimidin-5-yl]hepta-1,6-diynyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(50 mg, 60.0 umol) in THF (2 mL) was added Pd/C (5 mg, 12.0 umol, 10%purity) and Pd(OH)₂/C (5 mg, 12.0 umol, 20% purity) under N₂ atmosphere.The suspension was degassed and purged with H₂ for 3 times. The mixturewas stirred under H₂ (15 Psi) at 25° C. for 12 hrs. The reaction mixturewas filtered and concentrated under reduced pressure to give a residue.The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*30 mm*4 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 30%-60%, 10min) to give the title compound (12.0 mg, 26% yield, HCl) as a yellowsolid. LC-MS (ESI+) m/z 751.5 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6)δ=11.22-11.10 (m, 1H), 8.52 (m, 1H), 8.39 (m, 1H), 8.30 (s, 2H), 8.02(s, 1H), 7.64-7.45 (m, 4H), 7.43-7.37 (m, 1H), 7.36-7.31 (m, 1H),7.27-7.21 (m, 1H), 7.08-7.03 (m, 1H), 7.01-6.95 (m, 1H), 6.94-6.65 (m,1H), 6.12-5.89 (m, 1H), 4.78 (d, J=1.6 Hz, 2H), 3.77-3.71 (m, 2H),3.31-3.25 (m, 2H), 3.11-2.97 (m, 2H), 2.76-2.71 (m, 2H), 2.44-2.40 (m,2H), 2.13-2.07 (m, 1H), 2.06-1.98 (m, 2H), 1.96-1.88 (m, 2H), 1.70-1.62(m, 2H), 1.55-1.47 (m, 2H), 1.36-1.26 (m, 6H).

Example 10. General Method B. Synthesis of3-[6-[3-[3-[2-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyrimidin-5-yl]propyl-methyl-amino]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(I-110)

Step 1:3-[6-[3-[3-[2-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyrimidin-5-yl]propyl-methyl-amino]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione

A mixture of2-[6-amino-5-[8-[5-[3-(methylamino)propyl]pyrimidin-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol(20 mg, 44.8 umol),3-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-6-yl]propanal (15 mg,44.8 umol), AcOH (269 ug, 4.48 umol), NaBH(OAc)₃ (28.5 mg, 134 umol) inTHF (1 mL), DMF (1 mL) was degassed and purged with N2 for 3 times, andthen the mixture was stirred at 25° C. for 12 hr under N2 atmosphere.The reaction mixture was filtered and concentrated under reducedpressure to give a residue. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.05% HCl)-ACN]; B %: 18%-38%, 11 min) to give the title compound (15mg, 41% yield, HCl) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ=11.15(s, 1H), 10.77 (d, J=1.2 Hz, 1H), 8.54 (m, 1H), 8.48-8.36 (m, 3H), 8.12(s, 1H), 7.58 (d, J=5.6 Hz, 1H), 7.54-7.46 (m, 2H), 7.44-7.37 (m, 2H),7.27 (m, 1H), 7.12 (m, 1H), 6.98 (t, J=7.4 Hz, 1H), 6.04 (d, J=7.8 Hz,1H), 4.88 (s, 2H), 3.34-2.90 (m, 9H), 2.90-2.63 (m, 7H), 2.58-2.52 (m,3H), 2.17-2.03 (m, 5H), 2.03-1.89 (m, 4H), LC/MS (ESI, m/z):[M+1]⁺=766.5.

Example 11. General Method C. Synthesis of3-[6-[3-[4-[2-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyrimidin-5-yl]-1-piperidyl]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(I-138)

Step 1: tert-butyl4-[2-[3-[3-amino-6-(2-benzyloxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyrimidin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate

A mixture of6-(2-benzyloxyphenyl)-4-[8-(5-bromopyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-amine(8 g, 14.7 mmol), K₂CO₃ (6.09 g, 44.0 mmol), Pd(dppf)Cl₂ (537 mg, 0.734mmol) in dioxane (300 mL) was stirred at 25° C. for 0.16 h under N2atmosphere. Then tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(5.45 g, 17.6 mmol) and H₂O (37.5 mL) was added into the mixture, themixture was stirred at 80° C. for 11.83 h under N₂ atmosphere. Then themixture was diluted with H₂O (300 mL) and extracted with EtOAc (300mL*3), dried over sodium sulphate anhydrous, concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleumether/Ethyl acetate=1:0 to 0:1) to givethe title compound (6.3 g, 63% yield) as a yellow solid. LC-MS (ESI+)m/z 647.2 (M+H)+.

Step 2: tert-butyl4-[2-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyrimidin-5-yl]piperidine-1-carboxylate

A mixture of tert-butyl4-[2-[3-[3-amino-6-(2-benzyloxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyrimidin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate(3.2 g, 4.95 mmol), Pd/C (1.6 g, 10% purity), Pd(OH)₂/C (1.6 g, 20%purity) and formic acid (455 mg, 9.90 mmol) in THF (5 mL) was degassedand purged with N₂ for 3 times, and then the mixture was stirred at 25°C. for 12 h under H₂ atmosphere. The reaction mixture was filtered andconcentrated under reduced pressure to give the title compound (2.6 g,crude) was obtained as a yellow solid. LC-MS (ESI+) m/z 559.4 (M+H)+.

Step 3:2-[6-amino-5-[8-[5-(4-piperidyl)pyrimidin-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol

A mixture of tert-butyl4-[2-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyrimidin-5-yl]piperidine-1-carboxylate(2.6 g, 4.65 mmol) in HCl/dioxane (40 mL) and DCM (40 mL) was stirred at0° C. 10 min, and then it was stirred at 25° C. for 50 min. The reactionmixture was concentrated under reduced pressure to remove DCM andHCl/dioxane to give the title compound (2 g, crude, HCl) as a yellowsolid. LC-MS (ESI+) m/z 459.3 (M+H)+.

Step 4:3-[6-[3-[4-[2-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyrimidin-5-yl]-1-piperidyl]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione

A mixture of3-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-6-yl]propanal (40 mg,0.119 mmol),2-[6-amino-5-[8-[5-(4-piperidyl)pyrimidin-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol(54.7 mg, 0.119 mmol), NaBH(OAc)₃ (75.8 mg, 0.357 mmol), CH₃COOH (35.8mg, 0.596 mmol) in THF (2 mL) was degassed and purged with N2 for 3times, and then the mixture was stirred at 25° C. for 12 h under N₂atmosphere. The reaction mixture was concentrated under reduced pressureto give a residue. The residue was purified by prep-HPLC (column:Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.05%HCl)-ACN]; B %: 21%-41%, 11 min) to give the title compound (47.7 mg,48% yield) as a yellow solid. LC-MS (ESI+) m/z 778.5 (M+H)+. ¹H NMR (400MHz, DMSO-d6) δ=11.14 (s, 1H), 10.97-10.85 (m, 1H), 8.59-8.49 (m, 1H),8.41 (m, 1H), 8.38 (s, 2H), 8.13 (s, 1H), 7.61-7.55 (m, 1H), 7.54-7.47(m, 2H), 7.45-7.36 (m, 2H), 7.27 (m, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.97(m, 1H), 6.11-5.98 (m, 1H), 4.92-4.82 (m, 2H), 3.83-3.67 (m, 4H), 3.57(m, 2H), 3.27 (m, 2H), 3.13-2.95 (m, 6H), 2.84 (m, 2H), 2.78-2.65 (m,2H), 2.24-2.15 (m, 2H), 2.10 (m, 5H), 2.02-1.90 (m, 4H).

Example 12. General Method D. Synthesis of3-[6-[3-[4-[2-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-1-yl]ethyl]-1-piperidyl]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(I-122)

Step 1: tert-butyl4-[2-(p-tolylsulfonyloxy)ethyl]piperidine-1-carboxylate

A mixture of 4-methylbenzenesulfonyl chloride (6.23 g, 32.7 mmol),tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (5.00 g, 21.8mmol), TEA (6.62 g, 65.4 mmol) in DCM (45 mL) was degassed and purgedwith N2 for 3 times, and then the mixture was stirred at 25° C. for 12hr under N₂ atmosphere. The reaction mixture was partitioned between H₂O(50 mL) and Ethyl acetate (300 mL). The organic phase was separated,washed with brine 100 mL (50 mL*2), dried over Na₂SO₄, filtered,concentrated and purified by column chromatography (SiO₂,Petroleumether/Ethyl acetate=20/1) to give the title compound (7.00 g,82% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=7.80 (d, J=8.4Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 4.05 (t, J=6.4 Hz, 2H), 3.84 (d, J=12.8Hz, 2H), 2.59 (s, 2H), 2.43 (s, 3H), 1.55-1.40 (m, 5H), 1.38 (s, 9H),0.97-0.81 (m, 2H); LC-MS (ESI⁺) m/z 406.3 (M+Na)⁺.

Step 2: tert-butyl4-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethyl]piperidine-1-carboxylate

A mixture of tert-butyl4-[2-(p-tolylsulfonyloxy)ethyl]piperidine-1-carboxylate (3 g, 7.82mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.82g, 9.39 mmol), K₂CO₃ (3.24 g, 23.5 mmol),1,4,7,10,13,16-hexaoxacyclooctadecane (207 mg, 782 umol) in DMF (25 mL)was degassed and purged with N₂ for 3 times, and then the mixture wasstirred at 80° C. for 12 hr under N₂ atmosphere. The reaction mixturewas partitioned between H₂O (50 mL) and Ethyl acetate (200 mL). Theorganic phase was separated, washed with brine (20 mL), dried overNa₂SO₄, filtered, concentrated and purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=15/1) to give the title compound (2g, 48% yield) as a brown solid. LC-MS (ESI⁺) m/z 406.3 (M+H)⁺.

Step 3: tert-butyl4-[2-[4-(3-amino-6-chloro-pyridazin-4-yl)pyrazol-1-yl]ethyl]piperidine-1-carboxylate

A mixture of tert-butyl4-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethyl]piperidine-1-carboxylate(500 mg, 1.23 mmol), 4-bromo-6-chloro-pyridazin-3-amine (257 mg, 1.23mmol), Cs₂CO₃ (2 M, 1.85 mL), Pd(dppf)Cl₂—CH₂Cl₂ (50.4 mg, 61.7 umol) indioxane (5 mL) was degassed and purged with N2 for 3 times, and then themixture was stirred at 80° C. for 12 hr under N₂ atmosphere. Thereaction mixture was partitioned between H₂O 10 mL and Ethyl acetate 100mL. The organic phase was separated, washed with brine 20 mL, dried overNa₂SO₄, filtered, concentrated and purified by column chromatography(SiO₂, Petroleumether/Ethyl acetate=1:5) to give the title compound (340mg, 65% yield) as a yellow oil. LC-MS (ESI⁺) m/z 407.1 (M+H)⁺.

Step 4: tert-butyl4-[2-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-1-yl]ethyl]piperidine-1-carboxylate

A mixture of tert-butyl4-[2-[4-(3-amino-6-chloro-pyridazin-4-yl)pyrazol-1-yl]ethyl]piperidine-1-carboxylate(340 mg, 836 umol), (2-hydroxyphenyl)boronic acid (231 mg, 1.67 mmol),K₂CO₃ (346 mg, 2.51 mmol),[2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane(75.7 mg, 83.6 umol) in dioxane (10 mL) and H₂O (2 mL) was degassed andpurged with N2 for 3 times, and then the mixture was stirred at 80° C.for 12 hr under N₂ atmosphere. The reaction mixture was partitionedbetween H₂O 15 mL and Ethyl acetate 100 mL. The organic phase wasseparated, washed with brine 20 mL, dried over Na₂SO₄, filtered,concentrated and purified by column chromatography (SiO₂,Petroleumether/Ethyl acetate=3/1) to give the title compound (190 mg,48% yield) as a yellow solid. LC-MS (ESI⁺) m/z 465.3 (M+H)⁺.

Step 5:2-[6-amino-5-[1-[2-(4-piperidyl)ethyl]pyrazol-4-yl]pyridazin-3-yl]phenol

To a solution of tert-butyl4-[2-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-1-yl]ethyl]piperidine-1-carboxylate(190 mg, 409 umol) in DCM (3 mL) was added HCl/dioxane (4 M, 102 uL).The mixture was stirred at 25° C. for 1 hr. The reaction mixture wasconcentrated under reduced pressure to give the title compound (140 mg,crude) as a yellow solid. LC-MS (ESI⁺) m/z 365.2 (M+H)⁺.

Step 6:3-[6-[3-[4-[2-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-1-yl]ethyl]-1-piperidyl]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione

To a solution of2-[6-amino-5-[1-[2-(4-piperidyl)ethyl]pyrazol-4-yl]pyridazin-3-yl]phenol(40 mg, 99.8 umol),3-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-6-yl]propanal (33.5 mg,99.8 umol) and AcOH (30.0 mg, 499 umol) in THF (3 mL) and DMF (3 mL).The mixture was stirred at 25° C. for 0.5 hr. Then NaBH(OAc)₃ (63.4 mg,299 umol) was added at 25° C. The mixture was stirred at 25° C. for 12hr. The reaction mixture was quenched by addition H₂O 2 mL at 25° C.,and then concentrated and purified by prep-HPLC (column: PhenomenexSynergi C18 150*25*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %:21%-41%, 11 min) to give the title compound (38.0 mg, 52.5% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=11.15 (s, 1H), 8.54 (d, J=5.2Hz, 2H), 8.42 (d, J=4.4 Hz, 1H), 8.28 (s, 1H), 8.11 (s, 2H), 7.65-7.54(m, 2H), 7.44-7.35 (m, 2H), 7.27 (m, 1H), 7.14-7.05 (m, 1H), 6.99 (m,1H), 6.11-5.98 (m, 1H), 4.24 (m, 2H), 3.50-3.47 (m, 3H), 3.19-2.96 (m,4H), 2.93-2.77 (m, 4H), 2.12 (m, 4H), 1.98-1.74 (m, 5H), 1.70-1.39 (m,4H). LC-MS (ESI⁺) m/z 684.4 (M+H)⁺.

Example 13. General Method E. Synthesis of3-(5-(5-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)pentyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-136)

Step 1:3-(5-(5-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)pentyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of5-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-5-yl]pentanal (30 mg,0.083 mmol) and2-[6-amino-5-[1-(4-piperidyl)pyrazol-4-yl]pyridazin-3-yl]phenol (33.32mg, 0.099 mmol) in THF (1 mL) was added AcOH (25 mg, 0.41 mmol) andNaBH(OAc)₃ (53 mg, 0.25 mmol). The mixture was stirred at 25° C. for 1hr. The reaction mixture was quenched by H₂O 3 mL at 15° C., and thenconcentrated under reduced pressure to give a residue. The residue waspurified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 um;mobile phase: [water (0.1% TFA)-ACN]; B %: 12%-42%, 7 min), then addedHCl (2 mL, 1N) to give title compound (HCl, 20 mg, 28% yield, 99%purity) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=11.16 (s, 1H),10.86-10.78 (m, 1H), 8.51-8.43 (m, 3H), 8.29 (s, 1H), 8.14 (s, 1H), 7.60(m, 1H), 7.46-7.38 (m, 4H), 7.14-7.10 (m, 2H), 6.98 (s, 1H), 6.08-6.05(m, 1H), 4.58-4.53 (m, 1H), 3.23-3.07 (m, 9H), 2.73 (s, 2H), 2.42-2.33(m, 6H), 2.14-2.10 (s, 1H), 1.82 (s, 4H), 1.52 (m, 2H); LC-MS (ESI+) m/z684.2 (M+H)+.

Characterization data for further compounds prepared by Method E arepresented in Table 5 below. Compounds in Table 5 were prepared bymethods substantially similar to the steps described to prepare I-136.

TABLE 5 Compounds prepared according to Method E. LC/MS I-# (ESI, m/z)¹H NMR (400 MHz) I-133 [M + 1]⁺ = 1HNMR (400 MHz, DMSO-d6) δ = 11.16 (s,1 H), 10.93 (s, 1 H), 8.50- 670.5 8.69 (m, 2 H), 8.42 (s, 1 H),8.28-8.34 (m, 2 H), 8.01-8.22 (m, 2 H), 7.60 (d, J = 7.6 Hz, 2 H),7.34-7.47 (m, 2 H), 7.21-7.32 (m, 1 H), 7.12 (d, J = 8.0 Hz, 1 H), 6.99(t, J = 7.2 Hz, 1 H), 6.06 (s, 1 H), 4.57 (s, 1H), 3.62 (d, J = 11.2 Hz,2 H), 3.41 (s, 1 H), 2.94-3.28 (m, 6 H), 2.65-2.87 (m, 3 H), 2.26- 2.46(m, 4 H), 2.13 (s, 1 H), 1.83-1.74 (m, 4 H). I-134 [M + 1]⁺ = 1H NMR(400 MHz, DMSO-d6) δ = 11.15 (s, 1 H), 10.57 (s, 1 H), 8.50- 684.6 8.59(m, 2 H), 8.41 (d, J = 4.4 Hz, 1 H), 8.29 (s, 1 H), 8.11 (d, J = 18.0Hz, 3 H), 7.59 (d, J = 7.2 Hz, 2 H), 7.38 (s, 2 H), 7.23-7.31 (m, 1 H),7.14 (d, J = 8.4 Hz, 1 H), 6.98 (t, J = 7.60 Hz, 1 H), 6.06 (s, 1 H),4.13 (m, 3 H), 3.44 (d, J = 10.0 Hz, 2 H), 2.98-3.28 (m, 4 H), 2.87-2.50(m, 5 H), 2.11 (m, 2 H), 1.71 (m, 8H). I-135 [M + 1]⁺ = 1H NMR (400 MHz,DMSO-d6) δ = 11.14 (s, 1H), 11.03-10.88 (m, 1H), 684.2 8.55 (dd, J =1.2, 7.6 Hz, 1H), 8.51 (s, 1H), 8.40 (dd, J = 1.2, 4.8 Hz, 1H), 8.29 (s,1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.59 (dd, J = 1.6, 7.6 Hz, 1H), 7.56-7.50 (m, 1H), 7.41-7.35 (m, 2H), 7.25 (dd, J = 4.8, 7.6 Hz, 1H),7.13-7.07 (m, 1H), 6.98 (t, J = 7.2 Hz, 1H), 6.12-5.94 (m, 1H),4.60-4.50 (m, 1H), 3.42-3.37 (m, 1H), 3.17-2.97 (m, 7H), 2.82-2.75 (m,2H), 2.74-2.65 (m, 2H), 2.46-2.36 (m, 3H), 2.35-2.26 (m, 2H), 2.16-2.08(m, 1H), 1.88- 1.77 (m, 2H), 1.75-1.66 (m, 2H), 1.44-1.31 (m, 2H). I-137[M + 1]⁺ = 1H NMR (400 MHz, DMSO-d6) δ = 11.14 (s, 1H), 10.93 (d, J =6.4 Hz, 684.4 1H), 8.50 (s, 1H), 8.34 (d, J = 4.8 Hz, 1H), 8.29 (s, 1H),8.19-8.12 (m, 3H), 7.65 (d, J = 3.2 Hz, 1H), 7.61-7.57 (m, 1H), 7.53 (t,J = 7.6 Hz, 1H), 7.36 (td, J = 7.6, 15.6 Hz, 2H), 7.17-7.07 (m, 2H),6.98 (t, J = 7.6 Hz, 1H), 6.15- 5.99 (m, 1H), 4.61-4.49 (m, 2H), 3.61(d, J = 11.6 Hz, 2H), 3.28-3.19 (m, 2H), 3.17-2.96 (m, 6H), 2.75-2.65(m, 1H), 2.45-2.39 (m, 2H), 2.35- 2.27 (m, 2H), 2.15-2.06 (m, 1H), 1.84(s, 4H), 1.52 (d, J = 6.0 Hz, 2H).

Example 14. General Method F. Synthesis of3-(5-(3-((3-(2-(4-(3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-5-yl)piperidin-1-yl)pyrimidin-5-yl)propyl)(methyl)amino)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(I-139)

Step 1: methyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)benzoate

To a solution of 4-[2-(tert-butoxycarbonylamino)ethyl]benzoic acid (3 g,11.31 mmol) in DMF (40 mL) was added NaH (1.36 g, 60% purity, 3 eq) at0° C. and stirred at 20° C. for 1 hr. Then the mixture was added MeI(16.1 g, 113 mmol, 10 eq) at 0° C. The mixture was stirred at 20° C. for12 hr. The reaction mixture was quenched by addition H₂O (100 mL) at 0°C., and then diluted with water (100 mL) and extracted with EA (200mL*3). The combined organic layers were washed with brine (100 mL*6),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO2,Petroleum ether/Ethyl acetate=20/1 to 15/1) to give the title compound(1.95 g, 48% yield, 81% purity) as a off-white oil. ¹H NMR (400 MHz,DMSO-d6) δ=1.22-1.41 (m, 9H), 2.75 (s, 3H), 2.84 (2H), 3.38-3.47 (m,2H), 3.84 (s, 3H), 7.35 (m, 2H), 7.89 (d, J=8.0 Hz, 2H).

Step 2: tert-butyl 4-(hydroxymethyl)phenethyl(methyl)carbamate

To a solution of methyl4-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]benzoate (1.95 g, 6.65mmol) in THF (40 mL) was added LiBH₄ (290 mg, 13.3 mmol) at 0° C. Themixture was stirred at 25° C. for 12 hr. The reaction mixture wasquenched by addition H₂O (20 mL) at 0° C., and then diluted with water(30 mL) and extracted with EA (80 mL*3). The combined organic layerswere washed with brine (60 mL*3), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the title compound (1.6 g,crude) as a off-white oil. ¹H NMR (400 MHz, DMSO-d6) δ=1.28-1.42 (m,9H), 2.70-2.73 (m, 2H), 2.74 (s, 3H), 3.34-3.38 (m, 2H), 4.44-4.48 (m,2H), 5.10 (m, 1H), 7.12-7.19 (m, 2H), 7.21-7.27 (m, 2H).

Step 3: tert-butyl 4-(chloromethyl)phenethyl(methyl)carbamate

To a solution of tert-butylN-[2-[4-(hydroxymethyl)phenyl]ethyl]-N-methyl-carbamate (1.6 g, 6.03mmol) in DCM (30 mL) was added TEA (1.22 g, 12.1 mmol) and MsCl (1.04 g,9.04 mmol) at 0° C. The mixture was stirred at 25° C. for 4 hr. Thereaction mixture was quenched by addition H₂O (20 mL) at 25° C., andthen diluted with water (60 mL) and extracted with DCM (100 mL*3). Thecombined organic layers were washed with brine (80 mL*3), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thetitle compound (1.8 g, crude) as a yellow oil. ¹H NMR (400 MHz, DMSO-d6)δ=1.25-1.39 (m, 9H), 2.72-2.74 (m, 1H), 2.75 (s, 3H), 2.76-2.78 (m, 1H),3.36-3.41 (m, 2H), 4.73 (s, 2H), 7.14-7.24 (m, 2H), 7.36 (m, 2H).

Step 4: tert-butyl methyl(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)phenethyl)carbamate

To a solution of tert-butyl tert-butyl4-(chloromethyl)phenethyl(methyl)carbamate (1.2 g, 4.23 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (820 mg,4.23 mmol) in DMF (15 mL) was added K₂CO₃ (1.17 g, 8.46 mmol) and 18-C-6(112 mg, 423 umol). The mixture was stirred at 50° C. for 12 hr. Thereaction mixture was quenched by addition H₂O (20 mL) at 25° C., andthen diluted with water (100 mL) and extracted with EA (100 mL*3). Thecombined organic layers were washed with brine (80 mL*3), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO2,Petroleumether/Ethyl acetate=10/1 to 2/1) to give the title compound(1.25 g, 58% yield) as a off-white oil. ¹H NMR (400 MHz, DMSO-d6)δ=1.15-1.22 (m, 6H), 1.24 (s, 12H), 1.35 (s, 3H), 2.69-2.73 (m, 2H),2.74 (s, 3H), 3.33-3.38 (m, 2H), 5.29 (s, 2H), 7.13-7.16 (m, 2H),7.16-7.22 (m, 2H), 7.58 (s, 1H), 7.98 (s, 1H); LC/MS (ESI, m/z):[M+1]⁺=442.5.

Step 5: tert-butyl4-((4-(3-amino-6-chloropyridazin-4-yl)-1H-pyrazol-1-yl)methyl)phenethyl(methyl)carbamate

To a solution of 4-bromo-6-chloro-pyridazin-3-amine (460 mg, 2.21 mmol)and tert-butylmethyl(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1yl)methyl)phenethyl)carbamate (1.25 g, 2.21 mmol) in 1,4-dioxane (15 mL) was addedPd(dppf)Cl₂.CH₂Cl₂ (180 mg, 221 umol) and Cs₂CO₃ (2 M, 2 eq). Themixture was stirred at 80° C. for 12 hrs. The reaction mixture wasquenched by addition H₂O (10 mL) at 25° C., and then diluted with water(80 mL) and extracted with EA (100 mL*3). The combined organic layerswere washed with brine (60 mL*3), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, Petroleumether/Ethylacetate=5/1 to 1/2) to give the title compound (900 mg, 86% yield) as ayellow solid. LC/MS (ESI, m/z): [M+1]⁺=443.3.

Step 6: tert-butyl4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)methyl)phenethyl(methyl)carbamate

A mixture of tert-butyl4-((4-(3-amino-6-chloropyridazin-4-yl)-1H-pyrazol-1-yl)methyl)phenethyl(methyl)carbamate(900 mg, 2.03 mmol), (2-hydroxyphenyl)boronic acid (841 mg, 6.10 mmol),BrettPhos Pd G3 (184 mg, 203 umol, 0.1 eq) and K₂CO₃ (842 mg, 3 eq) indioxane (20 mL) and H₂O (4 mL) was degassed and purged with N2 for 3times, and then the mixture was stirred at 80° C. for 12 hr under N₂atmosphere. The reaction mixture was quenched by addition H₂O (10 mL) at25° C., and then diluted with water (50 mL) and extracted with EA (80mL*3). The combined organic layers were washed with brine (60 mL*3),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO2,Petroleumether/Ethyl acetate=4/1 to 1/2) to give the title compound (700mg, 69% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=1.24-1.37(m, 9H), 2.70-2.74 (m, 2H), 2.75 (s, 3H), 3.35-3.38 (m, 2H), 5.37 (s,2H), 6.50 (s, 2H), 6.89-6.95 (m, 2H), 7.01-7.12 (m, 1H), 7.17=7.22 (m,2H), 7.23-7.35 (m, 4H), 8.20 (m, 1H), 8.55-8.59 (m, 1H), 13.8 (s, 1H);LC/MS (ESI, m/z): [M+1]⁺=501.3.

Step 7:2-(6-amino-5-(1-(4-(2-(methylamino)ethyl)benzyl)-1H-pyrazol-4-yl)pyridazin-3-yl)phenol

To a solution of tert-butyl4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)methyl)phenethyl(methyl)carbamate(300 mg, 1 eq) in DCM (5 mL) was added HCl/dioxane (2 M, 5.00 mL). Themixture was stirred at 25° C. for 1 hr. The solvent was removed underreduced pressure to give the title compound (340 mg, crude, HCl) as ayellow solid. ¹H NMR (400 MHz, DMSO-d6) δ=2.37 (s, 3H), 2.74-2.84 (m,4H), 5.37 (s, 2H), 5.76 (s, 1H), 6.50 (s, 2H), 6.90-6.95 (m, 2H),7.21-7.24 (m, 2H), 7.24-7.28 (m, 1H), 7.28-7.32 (m, 2H), 7.98-8.05 (m,1H), 8.20 (d, J=4.0 Hz, 2H), 8.58 (s, 1H), 13.81 (s, 1H); LC/MS (ESI,m/z): [M+1]⁺=401.2.

Step 8:3-(6-(((4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)methyl)phenethyl)(methyl)amino)methyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-139)

A mixture of2-[6-amino-5-[1-[[4-[2-(methylamino)ethyl]phenyl]methyl]pyrazol-4-yl]pyridazin-3-yl]phenol(90 mg, 225 umol),9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indole-6-carbaldehyde (69.1 mg,225 umol, 1 eq), KOAc (88.2 mg, 899 umol, 4 eq) and AcOH (27.0 mg, 25.7uL, 2 eq) in DCM (1 mL) and i-PrOH (1 mL) was degassed and purged withN2 for 3 times, and then the mixture was stirred at 50° C. for 12 hrunder N₂ atmosphere. Then NaBH₃CN (42.4 mg, 3 eq) was added, theresultant mixture was stirred at 50° C. for 12 hr. The reaction mixturewas quenched by addition H₂O (0.5 mL) at 25° C. The reaction mixture wasconcentrated under reduced pressure to remove DCM and iPrOH. The residuewas purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 um; mobilephase: [water (10 mM NH₄HCO₃)-ACN]; B %: 32%-62%, 10 min) to give thetitle compound (18.5 mg, 11% yield) as a white solid. 1H NMR (400 MHz,DMSO-d6) δ=2.08-2.16 (m, 1H), 2.23 (s, 3H), 2.57-2.65 (m, 2H), 2.76-2.85(m, 2H), 2.97-3.15 (m, 2H), 3.68 (s, 2H), 5.35 (s, 2H), 6.02 (s, 1H),6.49 (s, 2H), 6.89-6.94 (m, 2H), 7.20-7.24 (m, 2H), 7.24-7.29 (m, 4H),7.39-7.47 (m, 1H), 7.51-7.58 (m, 1H), 7.97-8.02 (m, 1H), 8.08 (s, 1H),8.19 (d, J=4.0 Hz, 2H), 8.39-8.42 (m, 1H), 8.51-8.54 (m, 1H), 8.57 (s,1H), 11.14 (s, 1H), 13.81 (s, 1H); LC/MS (ESI, m/z): [M+1]⁺=692.4.

Example 15. General Method G.3-(6-(4-(5-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)methyl)-1,3-dioxan-2-yl)butyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-140)

Step 1:1-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A mixture of (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate (2.4g, 10.7 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.38 g,7.13 mmol), K₂CO₃ (2.96 g, 21.4 mmol),1,4,7,10,13,16-hexaoxacyclooctadecane (189 mg, 713 umol) in DMF (20 mL)was degassed and purged with N2 for 3 times, and then the mixture wasstirred at 80° C. for 12 hrs under N₂ atmosphere. The reaction mixturewas diluted with H₂O (50 mL) and extracted with EA (50 mL*3). Thecombined organic layers were washed with saturated brine (150 mL*6),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive the title compound (2.5 g, crude) as a brown solid. ¹H NMR (400MHz, DMSO-d₆) δ=7.91 (s, 1H), 7.59 (s, 1H), 4.21 (d, J=7.6 Hz, 2H), 3.81(dd, J=4.0, 12.0 Hz, 2H), 3.66 (dd, J=5.6, 12.0 Hz, 1H), 3.47 (dd,J=5.6, 12.0 Hz, 2H), 1.32 (s, 6H), 1.24 (s, 12H); LC-MS (ESI+) m/z 323.0(M+H)⁺.

Step 2:2-((4-(3-amino-6-chloropyridazin-4-yl)-1H-pyrazol-1-yl)methyl)propane-1,3-diol

A mixture of1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole(2 g, 6.21 mmol), 4-bromo-6-chloro-pyridazin-3-amine (863 mg, 4.14mmol), Pd(dppf)C12.CH₂C12 (338 mg, 414 umol), Cs₂CO₃ (2 M, 6.21 mL) indioxane (15 mL) was degassed and purged with N2 for 3 times, and thenthe mixture was stirred at 80° C. for 8 hrs under N₂ atmosphere. Thereaction mixture was diluted with H₂O (50 mL) and extracted with EA (50mL*3). The combined organic layers were washed with saturated brine (150mL*3), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by reversed-phaseflash (0.1% FA condition) to give the title compound (1.6 g, crude) as abrown solid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.32 (s, 1H), 8.05 (s, 1H),7.59 (s, 1H), 6.35 (s, 2H), 4.21 (d, J=5.6 Hz, 1H), 4.16 (d, J=6.8 Hz,2H), 4.10 (d, J=7.2 Hz, 1H), 3.39-3.37 (m, 4H), 2.13-2.07 (m, 1H); LC-MS(ESI+) m/z 284.1 (M+H)⁺.

Step 3:2-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)methyl)propane-1,3-diol

A mixture of2-[[4-(3-amino-6-chloro-pyridazin-4-yl)pyrazol-1-yl]methyl]propane-1,3-diol(1.5 g, 5.29 mmol), (2-hydroxyphenyl)boronic acid (2.19 g, 15.9 mmol),BrettPhos Pd G3 (479 mg, 529 umol) and K₂CO₃ (2.19 g, 15.9 mmol) indioxane (15 mL) and H₂O (3 mL) was degassed and purged with N2 for 3times, and then the mixture was stirred at 80° C. for 12 hr under N₂atmosphere. The reaction mixture was diluted with H₂O 80 mL andextracted with EA (80 mL*3). The combined organic layers were washedwith saturated brine (250 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by reversed-phase flash (0.1% FA condition) to give the titlecompound (600 mg, 29% yield) as a green solid. ¹H NMR (400 MHz, DMSO-d₆)δ=9.35-9.13 (m, 1H), 8.19 (d, J=14.4 Hz, 1H), 7.31-7.20 (m, 1H),7.18-7.13 (m, 1H), 7.08-7.01 (m, 1H), 6.95-6.89 (m, 2H), 6.78-6.72 (m,2H), 6.48 (s, 1H), 4.64-4.55 (m, 2H), 4.23-4.15 (m, 2H), 3.46-3.36 (m,4H), 2.18-2.09 (m, 1H); LC-MS (ESI+) m/z 342.3 (M+H)⁺.

Step 4:3-(6-(4-(5-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)methyl)-1,3-dioxan-2-yl)butyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-140)

To a solution of2-[[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-1-yl]methyl]propane-1,3-diol(50 mg, 129 umol, FA) and5-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-6-yl]pentanal (31.3 mg,86.1 umol) in toluene (3 mL) and DMF (1 mL) was added TsOH (1.48 mg,8.60 umol) and 4 A MOLECULAR SIEVE (50 mg). The mixture was stirred at110° C. for 4 hr. The mixture was concentrated under reduced pressure toremove toluene and filtered to collect the filtrate. The filtrate waspurified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 um; mobilephase: [water (10 mM NH₄HCO₃)-ACN]; B %: 32%-62%, 10 min). The fractionwas concentrated under reduced pressure to remove ACN and lyophilized.The lyophilization was purified by prep-HPLC (column: Waters Xbridge150*25 mm*5 um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 42%-72%,10 min) to give the title compound (2.2 mg, 4% yield) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ=13.81 (d, J=6.0 Hz, 1H), 11.13 (s, 1H),8.54-8.51 (m, 1H), 8.39 (dd, J=1.6, 4.8 Hz, 1H), 8.22-8.14 (m, 2H),8.07-7.97 (m, 2H), 7.50 (s, 1H), 7.38-7.32 (m, 1H), 7.29-7.22 (m, 2H),6.95-6.88 (m, 2H), 6.49 (s, 2H), 6.11-5.88 (m, 1H), 4.50-4.40 (m, 2H),4.04-3.75 (m, 4H), 3.49 (t, J=11.2 Hz, 1H), 3.08-2.95 (m, 2H), 2.80-2.69(m, 3H), 2.16-2.03 (m, 2H), 1.77-1.33 (m, 7H); LC-MS (ESI+) m/z 687.3(M+H)⁺.

Example 16. General Method H.3-[6-[3-[(3S)-3-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-1-yl]-1-piperidyl]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(I-141)

Step 1: tert-butyl (3R)-3-(p-tolylsulfonyloxy)piperidine-1-carboxylate

A mixture of 4-methylbenzenesulfonyl chloride (14.2 g, 74.5 mmol),tert-butyl (3R)-3-hydroxypiperidine-1-carboxylate (10 g, 49.7 mmol), TEA(15.1 g, 149 mmol) in DCM (150 mL) was degassed and purged with N2 for 3times, and then the mixture was stirred at 25° C. for 12 hr under N₂atmosphere. The reaction mixture was partitioned between H₂O (200 mL)and Ethyl acetate (500 mL). The organic phase was separated, washed withbrine (150 mL*3), dried over Na₂SO₄, filtered, concentrated and purifiedby column chromatography (SiO₂, Petroleum ether/Ethyl acetate=15/1 to10/1) to give the title compound (11.6 g, 60% yield) as a brown solid.¹H NMR (400 MHz, DMSO-d₆) δ=7.81 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.0 Hz,2H), 4.46 (s, 1H), 3.60 (dd, J=3.2, 13.2 Hz, 2H), 3.42-3.33 (m, 2H),2.42 (s, 3H), 1.85-1.50 (m, 4H), 1.35 (s, 9H); LC-MS (ESI+) m/z 300.2(M−56)⁺.

Step 2:tert-butyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate

A mixture of tert-butyl(3R)-3-(p-tolylsulfonyloxy)piperidine-1-carboxylate (10.6 g, 29.8 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.94 g,35.8 mmol), K₂CO₃ (12.4 g, 89.5 mmol),1,4,7,10,13,16-hexaoxacyclooctadecane (788 mg, 2.98 mmol) in DMF (100mL) was degassed and purged with N2 for 3 times, and then the mixturewas stirred at 95° C. for 12 hr under N₂ atmosphere. The reactionmixture was partitioned between H₂O (150 mL) and EA (500 mL). Theorganic phase was separated, washed with brine (100 mL), dried overNa₂SO₄, filtered, concentrated and purified by column chromatography(SiO₂, Petroleumether/Ethyl acetate=20/1 to 10/1) to give the titlecompound (3.4 g, 24% yield) was obtained as a yellow oil. ¹H NMR (400MHz, DMSO-d₆) δ=8.02 (s, 1H), 7.62 (s, 1H), 3.75 (d, J=4.8 Hz, 2H), 3.61(d, J=12.8 Hz, 2H), 2.07-2.04 (m, 1H), 1.81 (d, J=7.6 Hz, 2H), 1.65-1.60(m, 2H), 1.25 (s, 9H), 1.08 (s, 12H); LC-MS (ESI+) m/z 322.1 (M−55)⁺.

Step 3:tert-butyl-3-[4-(3-amino-6-chloro-pyridazin-4-yl)pyrazol-1-yl]piperidine-1-carboxylate

A mixture oftert-butyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate(400 mg, 1.06 mmol), 4-bromo-6-chloro-pyridazin-3-amine (221 mg, 1.06mmol), Cs₂CO₃ (2 M, 1.59 mL), Pd(dppf)Cl₂.CH₂Cl₂ (43.3 mg, 53.0 umol) indioxane (4 mL) was degassed and purged with N2 for 3 times, and then themixture was stirred at 80° C. for 12 hrs under N₂ atmosphere. Thereaction mixture was partitioned between H₂O (10 mL) and ethyl acetate(100 mL). The organic phase was separated, washed with brine (20 mL),dried over Na₂SO₄, filtered, concentrated and purified by columnchromatography (SiO₂, Petroleumether/Ethyl acetate=10/1 to 1/1) to givethe title compound (100 mg, 24% yield) as a yellow solid. LC-MS (ESI+)m/z 379.1 (M+H)⁺.

Step 4:tert-butyl-3-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-1-yl]piperidine-1-carboxylate

A mixture oftert-butyl-3-[4-(3-amino-6-chloro-pyridazin-4-yl)pyrazol-1-yl]piperidine-1-carboxylate(100 mg, 264 umol), (2-hydroxyphenyl)boronic acid (72.8 mg, 528 umol),K₂CO₃ (109 mg, 792 umol),[2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane(23.9 mg, 26.4 umol) in dioxane (5 mL) and H₂O (1 mL) was degassed andpurged with N2 for 3 times, and then the mixture was stirred at 80° C.for 12 hr under N₂ atmosphere. The reaction mixture was partitionedbetween H₂O (4 mL) and ethyl acetate (50 mL). The organic phase wasseparated, washed with brine (20 mL), dried over Na₂SO₄, filtered,concentrated and purified by column chromatography (SiO₂,Petroleumether/Ethyl acetate=10/1 to 1/1) to give the title compound (60mg, 52% yield) as a yellow solid. LC-MS (ESI+) m/z 437.3 (M+H)⁺.

Step 5: 2-[6-amino-5-[1-[3-piperidyl]pyrazol-4-yl]pyridazin-3-yl]phenol

To a solution oftert-butyl-3-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-1-yl]piperidine-1-carboxylate(60 mg, 137 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 34.4 uL).The mixture was stirred at 25° C. for 0.5 hr. The reaction mixture wasconcentrated under reduced pressure to give the title compound (40 mg,crude, HCl) as a yellow solid. LC-MS (ESI⁺) m/z 337.2 (M+H)⁺.

Step 6:3-[6-[3-[3-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-1-yl]-1-piperidyl]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(I-141)

To a solution of2-[6-amino-5-[1-[3-piperidyl]pyrazol-4-yl]pyridazin-3-yl]phenol (40 mg,107 umol), 3-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-6-yl]propanal(36.0 mg, 107 umol) and AcOH (32.2 mg, 536 umol) in DMF (3 mL) and THF(3 mL) was stirred 0.5 hr. Then NaBH(OAc)₃ (68.2 mg, 322 umol) was addedat 25° C. The mixture was stirred at 25° C. for 12 hr. The reactionmixture was quenched by addition H₂O (1 mL) at 25° C., and thenconcentrated and purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 19%-39%, 9.5min) to give the title compound (19.3 mg, 26% yield) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ=11.16 (s, 1H), 8.59-8.50 (m, 2H), 8.42 (d,J=2.8 Hz, 1H), 8.28 (s, 1H), 8.17 (d, J=4.8 Hz, 1H), 8.12 (s, 1H),7.59-7.59 (m, 1H), 7.67-7.50 (m, 1H), 7.47-7.33 (m, 2H), 7.26 (d, J=5.2Hz, 1H), 7.13-7.04 (m, 1H), 7.02-6.94 (m, 1H), 6.16-5.94 (m, 1H),5.07-4.85 (m, 1H), 3.79 (d, J=10.8 Hz, 3H), 3.24-3.13 (m, 3H), 3.09-2.95(m, 3H), 2.84 (s, 2H), 2.72 (d, J=6.4 Hz, 1H), 2.29-1.87 (m, 9H); LC-MS(ESI⁺) m/z 656.5 (M+H)⁺.

I-142 was prepared by a similar method as I-141. The S-chiral center ofthe starting material may racemize under the reaction conditions. 1H NMR(400 MHz, DMSO-d6) δ=11.57-11.40 (m, 1H), 11.19-11.10 (m, 1H), 8.62-8.50(m, 2H), 8.42 (dd, J=1.2, 4.8 Hz, 1H), 8.29 (s, 1H), 8.23-8.04 (m, 3H),7.65-7.53 (m, 2H), 7.46-7.35 (m, 2H), 7.30-7.23 (m, 1H), 7.12-7.05 (m,1H), 6.99 (t, J=7.6 Hz, 1H), 6.15-5.91 (m, 1H), 4.98-4.88 (m, 1H), 3.80(d, J=10.0 Hz, 2H), 3.56 (d, J=11.6 Hz, 1H), 3.38-3.28 (m, 1H),3.23-3.14 (m, 2H), 3.12-2.93 (m, 3H), 2.88-2.80 (m, 2H), 2.69 (d, J=3.2Hz, 1H), 2.29-2.17 (m, 3H), 2.15-1.97 (m, 4H). LC-MS (ESI+) m/z 656.4(M+H)⁺.

Example 17. General Method I.3-(4-(3-(4-(2-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-5-yl)piperidin-1-yl)propyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-145)

Step 1: 3-(4-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

A mixture of 3-(4-bromopyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (500mg, 1.40 mmol), tert-butyl-dimethyl-prop-2-ynoxy-silane (713 mg, 4.19mmol), Pd(PPh3)4 (161 mg, 140 umol), CuI (53.2 mg, 279 umol) and TEA(706 mg, 6.98 mmol) in DMSO (10 mL) was degassed and purged with N2 for3 times, and then the mixture was stirred at 85° C. for 12 hours underN2 atmosphere. The reaction mixture was diluted with ethyl acetate (100mL) and brine (100 mL). Then the aqueous layer was extracted with ethylacetate (50 mL). The organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 1/2) to givethe title compound (600 mg, 79% yield) as a yellow solid. LC-MS (ESI⁺)m/z=448.2 (M+H)⁺.

Step 2:3-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of3-[4-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(400 mg, 894 umol) in THF (10 mL) was added PtO₂ (101 mg, 447 umol).Then the mixture was stirred at 15° C. for 120 hours under H2atmosphere. The reaction mixture was filtered and concentrated to givethe title compound (400 mg, crude) as a black brown solid. LC-MS (ESI⁺)m/z=452.3 (M+H)⁺.

Step 3:3-(4-(3-hydroxypropyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of3-[4-[3-[tert-butyl(dimethyl)silyl]oxypropyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(400 mg, 886 umol) in DCM (15 mL) was added HCl/dioxane (4 M 177 uL).Then the mixture was stirred at 15° C. for 1 hour. The reaction mixturewas concentrated to give a residue. The residue was purified by reversedphase flash (FA) to give the title compound (250 mg, 84% yield) as awhite solid. 1H NMR (400 MHz, DMSO-d₆) δ=11.21 (s, 1H), 8.37 (d, J=4.8Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.75-7.64 (m, 1H), 7.57 (t, J=7.6 Hz,1H), 7.42-7.34 (m, 1H), 7.17 (d, J=5.2 Hz, 1H), 6.19-6.00 (m, 1H), 4.80(t, J=5.2 Hz, 1H), 3.68-3.60 (m, 5H), 3.31-3.24 (m, 2H), 3.12-3.06 (m,1H), 2.20-2.12 (m, 1H), 2.02-1.93 (m, 2H), 1.88-1.77 (m, 2H)._LC/MS(ESI, m/z): [M+1]+=338.1.

Step 4:3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-4-yl)propanal

To a solution of3-[4-(3-hydroxypropyl)pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione (50.0mg, 148 umol) in DCM (3 mL) was added DMP (94.3 mg, 222 umol). Then themixture was stirred at 0-15° C. for 12 hr. The reaction mixture wasdiluted with saturate NaHCO₃(2 mL) and Na₂S₂O₃ (2 mL). Then the reactionmixture was extracted with THF: ethyl acetate=1:1(10 mL×3). The organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated togive the title compound (30 mg, crude) as a colorless oil. LC/MS (ESI,m/z): [M+1]⁺=336.3.

Step 5:3-(4-(3-(4-(2-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-5-yl)piperidin-1-yl)propyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-145)

To a solution of3-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-4-yl]propanal (30.0 mg,89.5 umol) in DMF (1 mL) and THF (1 mL) was added2-[6-amino-5-[8-[5-(4-piperidyl)pyrimidin-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol(41.0 mg, 89.5 umol), AcOH (26.9 mg, 447 umol) and NaBH(OAc)₃ (56.9 mg,268 umol). Then the mixture was stirred at 25° C. for 3 hours. Thereaction mixture was quenched with H₂O (1 mL) and concentrated. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 20%-40%, 10min) to give the title compound (18.0 mg, 25% yield, HCl) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ=11.15 (s, 1H), 10.86 (dd, J=2.8, 7.6Hz, 1H), 8.55-8.15 (m, 4H), 7.76-7.60 (m, 1H), 7.59-7.45 (m, 3H),7.43-7.30 (m, 2H), 7.20 (s, 1H), 7.10 (d, J=7.2 Hz, 1H), 6.97 (s, 1H),6.21-5.97 (m, 1H), 4.91-4.75 (m, 2H), 3.60-3.54 (m, 3H), 3.28 (s, 6H),3.15-2.91 (m, 4H), 2.79-2.62 (m, 3H), 2.36-2.24 (m, 3H), 2.13-1.90 (m,9H). LC/MS (ESI, m/z): [M+1]⁺=778.4.

Characterization data for further compounds prepared by Method I arepresented in Table 6 below. Compounds in Table 6 were prepared bymethods substantially similar to the steps described to prepare I-145.

TABLE 1 Compounds prepared according to Method I. LC/MS I-# (ESI, m/z)¹H NMR (400 MHz) I-143 [M + 1]⁺ = ¹H NMR(400 MHz, DMSO-d₆) δ = 11.77 (s,1H), 11.15 (s, 1H), 8.62- 656.4 8.55 (m, 1H), 8.39-8.22 (m, 4H),8.17-8.10 (m, 1H), 7.66 (d, J = 1.2 Hz, 1H), 7.60-7.50 (m, 2H),7.41-7.29 (m, 2H), 7.20 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H),6.97 (t, J = 7.6 Hz, 1H), 6.18-6.01 (m, 1H), 4.95 (t, J = 11.2 Hz, 1H),3.80 (d, J = 9.2 Hz, 1H), 3.56 (d, J = 11.6 Hz, 1H), 3.39-3.28 (m, 4H),3.09-2.96 (m, 2H), 2.75-2.66 (m, 1H), 2.38-2.20 (m, 4H), 2.17-1.93 (m,5H).

Example 18. General Method J. 3-[5-[4-[4-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-1-yl]-1-piperidyl]cyclohexyl] pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione (I-147)

Step 1:3-[8-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrido[3,2-b]indol-5-yl]piperidine-2,6-dione

To a solution of 3-(5-bromopyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(1 g, 2.79 mmol) in dioxane (30 mL) was added2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.23 g, 8.38 mmol), K₂CO₃ (2 M, 4.19 mL), Pd(dppf)C12.CH₂Cl₂ (227 mg,279 umol), then mixture was stirred at 80° C. for 12 hours. Oncompletion, the reaction mixture was concentrated under reduced pressureto remove dioxane, The residue was purified by column chromatography(SiO₂, Petroleumether/Ethyl acetate=30:1) to give the title compound(420 mg, 34% yield) as a white solid. LC/MS (ESI, m/z): [M+1]⁺=418.2

Step 2:3-[8-(1,4-dioxaspiro[4.5]decan-8-yl)pyrido[3,2-b]indol-5-yl]piperidine-2,6-dione

To a solution of3-[8-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrido[3,2-b]indol-5-yl]piperidine-2,6-dione(420 mg, 1.01 mmol) in THF (10 mL) and DMF (10 mL) was added Pd/C (300mg, 10% purity), Pd(OH)₂/C (300 mg, 20% purity), then the mixture wasstirred at 25° C. for 48 hours under H2 atmosphere. On completion, thereaction mixture was filtered and concentrated under reduced pressure togive the title compound (400 mg, crude) as a yellow oil. LC/MS (ESI,m/z): [M+1]⁺=420.2

Step 3:3-[8-(4-oxocyclohexyl)pyrido[3,2-b]indol-5-yl]piperidine-2,6-dione

To a solution of3-[8-(1,4-dioxaspiro[4.5]decan-8-yl)pyrido[3,2-b]indol-5-yl]piperidine-2,6-dione(400 mg, 953 umol) in CH₃CN (20 mL) was added HCl/dioxane (4 M, 715 uL),then the mixture was stirred at 25° C. for 3 hours. On completion, thereaction mixture was concentrated under reduced pressure to removeCH₃CN, the mixture was diluted with water and was added DIEA until PH=7,filtered and concentrated under reduced pressure to give the titlecompound (310 mg, crude) as a white solid. LC/MS (ESI, m/z):[M+1]⁺=376.2

Step 4:3-[5-[4-[4-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-1-yl]-1-piperidyl]cyclohexyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(I-147)

To a solution of3-[8-(4-oxocyclohexyl)pyrido[3,2-b]indol-5-yl]piperidine-2,6-dione (270mg, 719 umol) in DCM (5 mL) and DMSO (5 mL) was added2-[6-amino-5-[1-(4-piperidyl)pyrazol-4-yl]pyridazin-3-yl]phenol (402 mg,1.08 mmol, HCl) and HOAc (43.1 mg, 719 umol), 4A MS (50 mg, 719.2 umol)at 110° C. for 12 hours, NaBH(OAc)₃ (457 mg, 2.16 mmol) was added tostirred at 25° C. for 2 hours. On completion, the reaction mixture wasconcentrated under reduced pressure to remove DCM. The residue wasdiluted with water (100 mL) and filtered and concentrated under reducedpressure to give a residue, The residue was purified by prep-HPLC(column: Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water(0.05% HCl)-ACN]; B %: 12%-42%, 10 min) to give the title compound (161mg, 30% yield, 98% purity, HCl) as a white solid. LC/MS (ESI, m/z):[M+1]⁺=696.4. ¹H NMR (400 MHz, DMSO-d₆) δ=11.16 (s, 1H), 11.02 (s, 1H),8.41-8.71 (m, 3H), 8.28-8.35 (m, 1H), 8.00-8.26 (m, 2H), 7.59-7.68 (m,1H), 7.44-7.58 (m, 2H), 7.36-7.43 (m, 1H), 7.36-7.43 (m, 1H), 7.33 (dd,J=7.6, 4.8 Hz, 1H), 7.14-7.27 (m, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.99 (t,J=7.6 Hz, 1H), 6.08 (s, 1H), 3.78 (s, 2H), 3.37 (d, J=11.2 Hz, 4H), 3.06(d, J=12.0 Hz, 2H), 2.52-2.78 (m, 3H), 2.28-2.48 (m, 5H), 1.90-2.25 (m,5H), 1.75 (m, 2H).

Characterization data for further compounds prepared by Method J arepresented in Table 7 below. Compounds in Table 7 were prepared bymethods substantially similar to the steps described to prepare I-147.

TABLE 7 Compounds prepared according to Method J. LC/MS I-# (ESI, m/z)¹H NMR (400 MHz) I-148 [M + 1]⁺ = ¹H NMR (400 MHz, DMSO-d₆) δ = 11.15(s, 1H), 11.02-10.88 (m, 696.1 1H), 8.53 (s, 1H), 8.42-8.34 (m, 1H),8.32 (s, 1H), 8.22-8.13 (m, 2H), 7.74-7.65 (m, 1H), 7.62 (dd, J = 1.6,8.0 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.43-7.30 (m, 2H), 7.20-7.13 (m,1H), 7.09 (d, J = 8.0 Hz, 1H), 7.03-6.95 (m, 1H), 6.19-5.96 (m, 1H),4.72-4.54 (m, 1H), 3.89-3.76 (m, 2H), 3.42-3.27 (m, 4H), 3.12-2.95 (m,2H), 2.78-2.54 (m, 3H), 2.45-2.30 (m, 5H), 2.27-1.93 (m, 6H), 1.87-1.66(m, 2H). I-144 [M + 1]⁺ = ¹H NMR (400 MHz, DMSO-d6) δ = 11.14 (s, 2H),8.63-8.45 (m, 2H), 696.2 8.42-8.41 (m, 1H), 8.33-8.28 (m, 1H), 8.15-8.11(m, 2H), 7.70-7.51 (m, 2H), 7.48-7.33 (m, 2H), 7.26-7.25 (m, 1H),7.13-7.09 (m, 1H), 7.04-6.91 (m, 1H), 6.16-5.90 (m, 1H), 4.99-4.70 (m,3H), 3.76-3.53 (m, 2H), 3.50-3.21 (m, 3H), 3.17-2.93 (m, 2H), 2.79-2.63(m, 2H), 2.42-2.26 (m, 5H), 2.18-1.94 (m, 4H), 1.88-1.60 (m, 4H).

Example 19. General Method K.3-(6-((4-((4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-146)

Step 1: 3-(6-vinyl-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

A mixture of 3-(6-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(500 mg, 1.40 mmol), potassium; trifluoro(vinyl)boranuide (563 mg, 4.20mmol, 3 eq), Cs₂CO₃ (2 M, 1.40 mL, 2 eq), Pd(dppf)C12.CH₂C12 (114 mg,0.1 eq) in 1,4-dioxane (10 mL) was degassed and purged with N2 for 3times, and then the mixture was stirred at 80° C. for 12 hr under N₂atmosphere. The reaction mixture was diluted with water 10 mL andextracted with ethyl acetate (20 mL*3). The combined organic layers werewashed with brine (20 mL*3), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, Petroleumether/Ethylacetate=3/1 to 1/1) to give the title compound (300 mg, 65% yield) wasobtained as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=306.5.

Step 2:9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indole-6-carbaldehyde

To a solution of 3-(6-vinylpyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(300 mg, 1 eq) in dioxane (5 mL) and H₂O (5 mL) was added2,6-dimethylpyridine (211 mg, 1.97 mmol, 2 eq), NaIO₄ (841 mg, 4 eq) andOsO₄ (25.0 mg, 0.1 eq). The mixture was stirred at 0° C. for 2 hr. Thereaction mixture was diluted with H₂O (30 mL) and extracted with EA (30mL*3). The combined organic layers were washed with Na₂SO₃ (100 mL*3)and saturated brine (100 mL*3), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, Petroleumether/Ethylacetate=1/1 to 0/1) to give the title compound (230 mg, 76% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d6) δ=2.14-2.28 (m, 1H), 2.67-2.77(m, 1H), 2.96-3.22 (m, 2H), 6.15 (s, 1H), 7.36-7.42 (m, 1H), 7.84 (d,J=4.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.52 (d, J=4.0 Hz, 1H), 8.72-8.76(m, 1H), 8.86 (s, 1H), 10.10 (s, 1H), 11.23 (s, 1H); LC/MS (ESI, m/z):[M+1]⁺=308.2.

Step 3:3-(6-(hydroxymethyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

A mixture of 9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indole-6-carbaldehyde(230 mg, 1 eq), NaBH(OAc)₃ (1.59 g, 10 eq), HOAc (225 mg, 5 eq) in DMF(6 mL) and DCM (6 mL) was degassed and purged with N2 for 3 times, andthen the mixture was stirred at 50° C. for 24 hr under N₂ atmosphere.The mixture was concentrated to remove the solvent to get residue. Theresidue was purified by reversed phase flash (0.1% FA) to give the titlecompound (200 mg, 86% yield) as a light yellow solid. LC/MS (ESI, m/z):[M+1]⁺=309.9.

Step 4:3-(6-(azidomethyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of3-[6-(hydroxymethyl)pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione (100mg, 1 eq) and [azido(phenoxy)phosphoryl]oxybenzene (178 mg, 2 eq) intoluene (4 mL) was added DBU (148 mg, 3 eq). The mixture was stirred at95° C. for 3 hr. The reaction mixture was quenched by addition H₂O (5mL) at 25° C., and then diluted with water (15 mL) and extracted withethyl acetate (20 mL*3). The combined organic layers were washed withbrine (20 mL*2), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleumether/Ethyl acetate=5/1 to 1/1) to givethe title compound (95 mg, 90% yield) as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ=1.28 (m, 1H), 2.29-2.39 (m, 1H), 2.96-3.02 (m, 3H), 4.54(s, 2H), 7.25-7.28 (m, 1H), 7.29-7.32 (m, 1H), 7.45-7.50 (m, 1H),8.07-8.10 (m, 1H), 8.27 (s, 1H), 8.36-8.40 (m, 1H), 8.46-8.49 (m, 1H);LC/MS (ESI, m/z): [M+1]⁺=335.1.

Step 5:2-(6-amino-5-(1-(1-(prop-2-yn-1-yl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridazin-3-yl)phenol

To a solution of2-[6-amino-5-[1-(4-piperidyl)pyrazol-4-yl]pyridazin-3-yl]phenol (200 mg,1 eq) 3-bromoprop-1-yne (70.7 mg, 1 eq) in DMF (6 mL) was added K₂CO₃(247 mg, 3 eq). The mixture was stirred at 25° C. for 12 hr. The residuewas diluted with water (20 mL) and extracted with EA (30 mL*3). Thecombined organic layers were washed with brine (30 mL*2), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-TLC (SiO₂, DCM:MeOH=20:1) togive the title compound (75 mg, 30% yield) as a yellow solid. ¹H NMR(400 MHz, DMSO-d6) δ=2.02-2.16 (m, 4H), 2.30-2.38 (m, 2H), 2.94 (m, 2H),3.20 (m, 1H), 3.35 (m, 2H), 4.15-4.25 (m, 1H), 6.52 (s, 2H), 6.90-6.96(m, 2H), 7.24-7.30 (m, 1H), 7.98-8.02 (m, 1H), 8.19 (d, J=16.0 Hz, 2H),8.49 (s, 1H), 13.84 (s, 1H); LC/MS (ESI, m/z): [M+1]⁺=375.2.

Step 6:3-(6-((4-((4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-146)

To a solution of2-(6-amino-5-(1-(1-(prop-2-yn-1-yl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridazin-3-yl)phenol(60 mg, 1 eq) and3-(6-(azidomethyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (53.6mg, 1 eq) in THF (3 mL) was added CuI (15.3 mg, 0.5 eq) and DIPEA (20.7mg, 1 eq). The mixture was stirred at 50° C. for 24 hr. The reactionmixture was concentrated under reduced pressure to remove THF. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*30mm*4 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 11%-41%, 10 min) togive the title compound (31.5 mg, 27% yield) as a yellow solid. ¹H NMR(400 MHz, DMSO-d6) δ=2.09-2.18 (m, 1H), 2.28-2.40 (m, 4H), 2.66-2.77 (m,2H), 2.95-3.15 (m, 3H), 3.16-3.37 (m, 4H), 4.44 (s, 2H), 4.50-4.60 (m,1H), 5.84 (s, 2H), 6.01-6.14 (m, 1H), 6.96-7.02 (m, 1H), 7.08 (m, 1H),7.26-7.33 (m, 1H), 7.36-7.43 (m, 1H), 7.58-7.71 (m, 3H), 8.11-8.18 (m,1H), 8.26-8.35 (m, 2H), 8.43-8.50 (m, 3H), 8.58-8.63 (m, 1H),11.04-11.18 (m, 2H); LC/MS (ESI, m/z): [M+1]⁺=709.4.

Remaining compounds I-75 to I-106, I-108, I-109, I-111 to I-121, andI-123 to I-132 were prepared according to methods substantially similarto those described above which would be readily apparent to those havingskill in the art.

Example 14. MSD SMARCA2 Degration in NCI-111299 Cell Line

Cell Line Vendor Medium NCI-H1299 ATCC RPMI MEDIUM 1640 + 10% FBS + 1xPS

Regents Vendor Cat# RPMI MEDIUM 1640 Invitrogen A10491-01 Fetal bovineserum (FBS) Hyclone SH30406.05 Penicillin-Streptomycin (100x) SolarBioP1400 Phosphate Buffered Saline Solarbio P1020-500 (PBS) RIPA Bufferwith EDTA BBP 115D cOmplete ULTRA Tablets, Roche Applied 05892791001Mini, EDTA-free, EASYpack Science MSD Standard Plate Meso ScaleDiscovery L15XA-3 Anti-SMARCA2/BRM antibody Abcam ab223735 SULFO-TAGanti-rabbit Meso Scale Discovery R32AB-5 antibody MSD Blocker A MesoScale Discovery R93BA-4 MSD Read Buffer T (4x) Meso Scale DiscoveryR92TC-1 Tris Buffered Saline with CST 9997S Tween ® 20 (TBST-10X)

Instrument Vendor Cat# Cell counter Invitrogen Countess CentrifugeEppendorf 5810R CO₂ Incubator Thermo Model: 371 Vortex IKA MS3 digitalEcho Liquid Handler Labcyte 550 TECAN TECAN Freedom EVO200 PERSONALPIPETTOR Apricot Designs PP5 + 1 MSD reader Meso Scale Discovery MSDSECTOR 6000 96 well plate Corning 3599 225 cm² Cell Culture Corning431081 Flask 50 mL centrifuge tube BD-Falcon 352098 15 mL centrifugetube BD-Falcon 352097

Cell Culture: Cells were cultured in exponential growth phase.

Compound Preparation and Treatment: NCI-H1299 cells were seeded into the96-well plate at 4.0*10⁴ cells per 100 ul per well. Incubate the platein the incubator overnight. The next day, compounds were diluted todesigned stock concentration by TECAN, then perform a 3 fold, 9-pointdilution via transferring 15 uL compound into 30 μL DMSO using Apricot.200 nL diluted compound from compound source plate were transferred intothe 96-intermediate plate as designated by using Echo550, followed with100 ul culture medium to make the 2X compound solution. Cell plate werechanged with 80 ul of fresh culture medium and 80 ul of 2X compoundsolution was added into the well to achieve the final designedconcentration. Cell plate was then shaken at 720 rpm for 5 min andincubated for 24 hours in the incubator.

Sample Preparation: Media was aspirated from the cultures and the platewas washed with PBS twice. 60 ul of pre-chilled PIPA lysis buffer(Boston BioProducts BP-115D) with protease inhibitor were directly addedinto the well to lyze the cells for 20 minutes at 4° C. Cell lysateswere collected.

MSD Procedure: The MSD plate was coated with 40 ul cell lysate andincubated at 4° C. overnight. The next day, the MSD coated bare platewas washed 3 times with 150 ul 1x TBST per well, blocked with 150 ul ofblocking buffer per well, and shaken for 1 hour at RT, 600 rpm. Blockingbuffer was 3% Blocker A in TBST. MSD plate was then washed 3 times with150 ul 1x TBST per well and Primary Detection antibody (Rabbitanti-SMARCA2/BRM antibody, 100 μg/ml, ab223735) was added to a final[conc.]: 0.3 ug/ml, 25 ul/well and shaken for 1 hour at RT, 600 rpm.Antibody was prepared in Antibody Detection buffer (1% Blocker A in1×TBST). The MSD plate was then washed 3 times with 150 ul 1×TBST perwell. Secondary Detection antibody (SULFO-TAG anti-species antibody) wasthen added to a final [conc.]: 1 ug/ml, 25 ul/well, and shaken for 1hour at RT, 600 rpm. Antibodies were prepared in Antibody Detectionbuffer (1% Blocker A in 1×TBST). MSD plate was washed 3 times with 150ul 1×TBST per well and 2X MSD reading buffer was added, 150 ul per well,and diluted from 4X with water. MSD instrument was then read.

Data Analysis: The percentage of relative level of SMARCA2 level wascalculated following equation below.

${\%\mspace{14mu}{Relative}\mspace{14mu}{Level}} = {100\% \times \frac{{{MSD}\mspace{14mu}{Signal}_{S{ample}}} - {{MSD}\mspace{14mu}{Signal}_{LC}}}{{{MSD}\mspace{14mu}{Singal}_{HC}} - {{MSD}\mspace{14mu}{Signal}_{LC}}}}$

LC: A2780, SMARCA2 negative cells. HC: NCI-H1299 cells treated withDMSO.

SMARCA2 protein degradation in H1299 cells for compounds of theinvention are presented in Table 8. The letter codes for SMARCA2degradation potency (DC50) include: A (<100 nM), B (100-500 nM), C(501-1000 nM), and D (>1000 nM). The letter codes for the percentage ofSMARCA2 degradation after 24 hours (Dmax %) include: A (>90%degradation), B (>70-90% degradation), C (50-70% degradation) and D(<50% degradation).

TABLE 8 SMARCA2 MSD H1299 Degradation Results. SMARCA2 MSD H1299 SMARCA2MSD H1299 degradation 24 h: Average degradation 24 h: Average I-#external-Abs IC50 (nM) Dmax % I-75 B B I-76 B A I-77 B A I-78 C C I-79 BC I-80 B A I-81 C B I-82 B B I-83 C B I-84 C C I-85 A A I-86 D D I-87 DD I-88 D B I-89 D D I-90 D D I-91 D D I-92 D D I-93 D D I-94 D C I-95 DD I-96 B C I-97 A A I-98 B A I-99 D D I-100 D D I-101 D D I-102 D CI-103 A A I-104 B A I-105 D D I-133 A A I-134 A B I-135 A C I-136 A —I-137 A A I-138 A A I-140 D D I-141 B B I-142 — D I-143 B A I-144 A AI-145 A A I-146 B B

Example 15. General Method L. Synthesis of3-[6-([2-[2-(2-[4-[(4-[7-[trans-4-hydroxycyclohexyl]-2-[(3,3,3-trifluoropropyl)amino]pyrrolo[2,3-d]pyrimidin-5-yl]phenyl)methyl]piperazin-1-yl]ethoxy)ethoxy]ethyl]amino)pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione;formic acid (I-153)

Step 1:3-[6-([2-[2-(2-hydroxyethoxy)ethoxy]ethyl]amino)pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione

To a stirred solution of3-[6-(11,11,12,12-tetramethyl-4,7,10-trioxa-1-aza-11-silatridecan-1-yl)pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(456 mg, 0.84 mmol) in DCM (10.0 mL) was added trifluoroacetic acid(1.00 mL) at 0° C. under nitrogen atmosphere. The reaction was stirredfor 1 h at room temperature. The resulting mixture was concentratedunder vacuum and the residue was purified by reversed phase flashchromatography with the following conditions: column WelFlash™ C18-I,20-40 um, 330 g; Eluent A: water (plus 10 mmol/L FA); Eluent B: ACN;Gradient: 25%-45% B in 20 min; Flow rate: 80 mL/min; Detector: UV220/254 nm; desired fractions were collected at 34% B and concentratedunder reduced pressure to afford3-[6-([2-[2-(2-hydroxyethoxy)ethoxy]ethyl]amino)pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(310 mg, 86%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s,1H), 8.46-8.37 (m, 1H), 8.35-8.30 (m, 1H), 8.05 (s, 1H), 7.40-7.26 (m,2H), 7.20-7.10 (m, 1H), 5.91 (s, 1H), 5.33 (t, J=5.9 Hz, 1H), 3.64-3.38(m, 12H), 3.03-2.96 (m, 3H), 2.07 (s, 1H). LC/MS (ESI, m/z):[(M+23)]⁺=427.30.

Step 2: tert-butylN-[9-(2,6-dioxopiperidin-3-yl)pyrido[2,3-b]indol-6-yl]-N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate

To a stirred solution of3-[6-([2-[2-(2-hydroxyethoxy)ethoxy]ethyl]amino)pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(270 mg, 0.63 mmol) in DCM (30.0 mL) was added Boc₂O (207 mg, 0.95 mmol)at room temperature under nitrogen atmosphere. The reaction was stirredfor 16 h at room temperature. Upon completion, the solution wasconcentrated under reduced pressure. The residue was purified byreversed phase flash chromatography with the following conditions:column WelFlash™ C18-I, 20-40 um, 330 g; Eluent A: water (plus 10 mmol/LFA); Eluent B: ACN; Gradient: 45%-65% B in 20 min; Flow rate: 80 mL/min;Detector: UV 220/254 nm; desired fractions were collected at 54% B andconcentrated under reduced pressure to afford tert-butylN-[9-(2,6-dioxopiperidin-3-yl)pyrido[2,3-b]indol-6-yl]-N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate(320 mg, 96%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.18 (s, 1H), 8.60-8.50 (m,1H), 8.49-8.37 (m, 1H), 8.14 (d, J=2.1 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H),7.45-7.35 (m, 1H), 7.30-7.20 (m, 1H), 6.04 (s, 1H), 4.57 (s, 1H), 3.79(t, J=6.0 Hz, 2H), 3.58-3.48 (m, 6H), 3.47 (d, J=4.6 Hz, 2H), 3.10-2.90(m, 2H), 2.76-2.63 (m, 3H), 2.18-2.00 (m, 1H), 1.59-1.19 (m, 9H). LC/MS(ESI, m/z): [(M+23)]⁺=527.30.

Step 3: tert-butyl(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)(2-(2-(2-oxoethoxy)ethoxy)ethyl)carbamate

To a stirred solution of oxalyl chloride (4 equiv.) in DCM was addedDMSO (5 equiv.) dropwise at −78° C. under nitrogen atmosphere. Theresulting solution was stirred for 30 min at −78° C. Then a solution of3-[5-[3-(4-hydroxybutoxy)propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl]piperidine-2,6-dione(1 equiv.) in DCM was added dropwise at −78° C. The resulting solutionwas stirred for another 30 min at the same temperature. Then TEA (10equiv.) was added at −78° C. The reaction temperature was slowlyincreased to room temperature in 30 min. The resulting mixture wasdiluted with water and extracted with DCM (3×). The combined organiclayers were dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified byreversed phase flash chromatography with the following conditions:Column: WelFlash™ C18-I, 20-40 um, 330 g; Eluent A: water (plus 10mmol/L FA); Eluent B: ACN; Flow rate: 80 mL/min; Detector: UV 220/254nm; desired fractions were collected and concentrated under reducedpressure to afford the title compound. LC/MS (ESI, m/z):[(M+1)]⁺=525.30.

Step 4: tert-butylN-[9-(2,6-dioxopiperidin-3-yl)pyrido[2,3-b]indol-6-yl]-N-[2-[2-(2-[4-[(4-[7-[trans-4-hydroxycyclohexyl]-2-[(3,3,3-trifluoropropyl)amino]pyrrolo[2,3-d]pyrimidin-5-yl]phenyl)methyl]piperazin-1-yl]ethoxy)ethoxy]ethyl]carbamate

To a stirred solution oftrans-4-[5-[4-(piperazin-1-ylmethyl)phenyl]-2-[(3,3,3-trifluoropropyl)amino]pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexan-1-olhydrochloride (37.0 mg, 0.074 mmol) and2-[2-(2-[[9-(2,6-dioxopiperidin-3-yl)pyrido[2,3-b]indol-6-yl]amino]ethoxy)ethoxy]acetaldehyde(38.6 mg, 0.074 mmol) in DCM (10.0 mL) was added KOAc (28.9 mg, 0.29mmol) at room temperature. Then NaBH(OAc)₃ (46.8 mg, 0.221 mmol) wasadded to the reaction. The reaction was stirred for 1 hour at roomtemperature. Upon completion, the solution was concentrated underreduced pressure and purified by reversed phase flash chromatograph withthe following conditions: Column: Xselect CSH OBD Column 30×150 mm 5 um;Mobile Phase A: water (plus 0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL/min; Gradient: 13% B to 22% B in 7 min; detector: 220/254 nm; desiredfractions were collected at 6.48 min and lyophilized to afford the titlecompounds (20.0 mg, 30%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.18 (s, 1H), 8.87 (s, 1H), 8.57 (dd, J=7.6, 1.7 Hz, 1H), 8.43 (dd,J=4.9, 1.6 Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.66-7.53 (m, 3H), 7.39 (d,J=8.7 Hz, 1H), 7.32-7.16 (m, 2H), 7.05 (t, J=5.8 Hz, 1H), 6.94-6.85 (s,1H), 6.04 (s, 1H), 4.70 (d, J=4.5 Hz, 1H), 4.50-4.37 (m, 1H), 3.86-3.63(m, 3H), 3.62-3.35 (m, 13H), 3.18-2.94 (m, 2H), 2.75-2.55 (m, 2H),2.50-2.20 (m, 13H), 2.15-2.04 (m, 1H), 2.04-1.53 (m, 6H), 1.31 (m, 9H).LC/MS (ESI, m/z): [(M+1)]⁺=1011.50.

Step 5:3-[6-([2-[2-(2-[4-[(4-[7-[trans-4-hydroxycyclohexyl]-2-[(3,3,3-trifluoropropyl)amino]pyrrolo[2,3-d]pyrimidin-5-yl]phenyl)methyl]piperazin-1-yl]ethoxy)ethoxy]ethyl]amino)pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione;Formic Acid

To a stirred solution of tert-butylN-[9-(2,6-dioxopiperidin-3-yl)pyrido[2,3-b]indol-6-yl]-N-[2-[2-(2-[4-[(4-[7-[trans-4-hydroxycyclohexyl]-2-[(3,3,3-trifluoropropyl)amino]pyrrolo[2,3-d]pyrimidin-5-yl]phenyl)methyl]piperazin-1-yl]ethoxy)ethoxy]ethyl]carbamate(20.0 mg, 0.02 mmol) in DCM (10.0 mL) was added HCl (4M) in 1,4-dioxane(2.00 mL) at room temperature under nitrogen atmosphere. The reactionwas reacted for 2 h and was concentrated under reduced pressure. Thecrude product (50 mg) was purified by Prep-HPLC with the followingconditions (Column: Xselect CSH OBD Column 30×150 mm 5 um; Mobile PhaseA: water (plus 0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min;Gradient: 13% B to 22% B in 7 min; detector: UV 220/254 nm; desiredfractions were collected at 6.48 min and lyophilized to affordtrans-3-[6-[14-(4-[7-[trans-4-hydroxycyclohexyl]-2-[(3,3,3-trifluoropropyl)amino]pyrrolo[2,3-d]pyrimidin-5-yl]phenyl)-4,7-dioxa-1,10,13-triazatetradecan-1-yl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione;formic acid (10.0 mg, 54%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.73 (s, 1H), 8.50 (s, 1H), 8.38 (dd, J=7.7, 1.6 Hz, 1H), 8.34 (dd,J=4.9, 1.6 Hz, 1H), 7.57-7.51 (m, 2H), 7.49 (d, J=2.3 Hz, 1H), 7.41 (s,1H), 7.32 (m, 1H), 7.28-7.21 (m, 2H), 7.17 (dd, J=7.6, 4.9 Hz, 1H), 7.01(m, 2.3 Hz, 1H), 5.92-5.85 (m, 1H), 4.55 (p, J=8.1 Hz, 1H), 3.81-3.65(m, 11H), 3.53 (s, 2H), 3.41 (t, J=5.2 Hz, 2H), 3.06-2.77 (m, 9H),2.70-2.50 (m, 6H), 2.18-1.99 (m, 7H), 1.54 (m, 2H). LC/MS (ESI, m/z):[(M/2+1)]⁺=456.55.

Characterization data for further compounds prepared by Method L arepresented in Table 9 below. Compounds in Table 9 were prepared bymethods substantially similar to the steps described to prepare I-153.

TABLE 9 Compounds prepared according to Method L. MS: I-# Name [(M +1)]⁺ ¹H NMR I-149 3-[6-[11-(4-[7-[trans-4- 842.35 (400 MHz, CD₃OD) δ8.86 (s, 1H), 8.59- hydroxycyclohexyl]-2-[(3,3,3- 8.48 (m, 2H), 8.39 (d,J = 2.2 Hz, 1H), 7.96 trifluoropropyl)amino]-7H- (s, 1H), 7.81 (d, J =8.9 Hz, 1H), 7.74 (d, J = pyrrolo[2,3-d]pyrimidin-5- 8.0 Hz, 2H), 7.69(dd, J = 8.8, 2.2 Hz, 1H), yl]phenyl)-4,7-dioxa-1,10- 7.64 (d, J = 8.0Hz, 2H), 7.33 (dd, J = 7.7, diazaundecan-1-yl]-9H- 4.9 Hz, 1H), 6.11 (d,J = 11.9 Hz, 1H), 4.66- pyrido[2,3-b]indol-9- 4.58 (m, 1H), 4.30 (s,2H), 3.91-3.78 (m, yl]piperidine-2,6-dione; 10H), 3.73 (t, J = 5.1 Hz,3H), 3.36-3.25 (m, trihydrochloride 4H), 3.13-3.04 (m, 1H), 2.94-2.85(m, 1H), 2.74-2.61 (m, 2H), 2.32-2.22 (m, 1H), 2.19- 2.01 (m, 6H), 1.55(p, J = 10.8 Hz, 2H) I-150 3-(6-[3-[2-(2-[4-[(4-[7-[trans-4- 910.35 (400MHz, CD3OD) δ 8.72 (s, 1H), 8.42 hydroxycyclohexyl]-2-[(3,3,3- (dd, J =7.6, 1.6 Hz, 1H), 8.37 (dd, J = 4.9, trifluoropropyl)amino]-7H- 1.6 Hz,1H), 7.99 (d, J = 1.6 Hz, 1H), 7.57- pyrrolo[2,3-d]pyrimidin-5- 7.50 (m,2H), 7.44-7.34 (m, 3H), 7.34-7.28 yl]phenyl)methyl]piperazin- (m, 2H),7.21 (dd, J = 7.7, 4.9 Hz, 1H), 5.95 1-yl]ethoxy)ethoxy]propyl]- (d, J =9.8 Hz, 1H), 4.53 (p, J = 8.2 Hz, 1H), 9H-pyrido[2,3-b]indol-9-3.79-3.58 (m, 10H), 3.56-3.47 (m, 4H), yl)piperidine-2,6-dione 3.19-2.95(m, 3H), 2.91-2.82 (m, 3H), 2.76- 2.46 (m, 11H), 2.26-1.91 (m, 10H),1.54- 1.52 (m, 2H), 1.31 (s, 1H) I-151 3-(4-[3-[2-(2-[4-[(4-[7-[trans-4-910.55 (400 MHz, CD3OD) δ 8.74 (s, 1H), 8.32-hydroxycyclohexyl]-2-[(3,3,3- 8.21 (m, 2H), 7.58-7.47 (m, 4H), 7.41 (s,trifluoropropyl)amino]-7H- 1H), 7.35-7.24 (m, 3H), 7.09 (d, J = 5.1 Hz,pyrrolo[2,3-d]pyrimidin-5- 1H), 5.99 (s, 1H), 4.55 (p, J = 8.5 Hz, 1H),yl]phenyl)methyl]piperazin- 3.79-3.56 (m, 12H), 3.48 (d, J = 4.3 Hz,2H), 1-yl]ethoxy)ethoxy]propyl]- 3.14-2.96 (m, 2H), 2.87-2.80 (m, 1H),2.77- 9H-pyrido[2,3-b]indol-9- 2.42 (m, 12H), 2.24-1.96 (m, 10H), 1.54(m, yl)piperidine-2,6-dione 2H), 1.31 (q, J = 8.4, 7.7 Hz, 1H) I-1523-(7-[3-[2-(2-[4-[(4-[7-[trans-4- 910.45 (400 MHz, CD3OD) δ 8.71 (s,1H), 8.35 (d, hydroxycyclohexyl]-2-[(3,3,3- J = 6.3 Hz, 2H), 8.01 (d, J= 8.0 Hz, 1H), trifluoropropyl)amino]-7H- 7.54 (d, J = 7.9 Hz, 2H),7.41-7.30 (m, 4H), pyrrolo[2,3-d]pyrimidin-5- 7.22-7.10 (m, 2H), 5.97(d, J = 11.2 Hz, 1H), yl]phenyl)methyl]piperazin- 4.57-4.49 (m, 1H),3.74-3.59 (m, 9H), 3.53- 1-yl]ethoxy)ethoxy]propyl]- 3.51 (m, 4H),3.19-2.96 (m, 3H), 2.92-2.83 9H-pyrido[2,3-b]indol-9- (m, 3H), 2.73-2.52(m, 11H), 2.16-1.93 (m, yl)piperidine-2,6-dione 9H), 1.55-1.53 (m, 2H),1.34-1.28 (m, 1H) I-154 3-(5-[3-[2-(2-[4-[(4-[7-[trans-4- 910.30 (400MHz, CD3OD) δ 8.74 (s, 1H), 8.60 hydroxycyclohexyl]-2-[(3,3,3- (dd, J =7.9, 1.5 Hz, 1H), 8.38 (dd, J = 4.9, trifluoropropyl)amino]pyrrolo[2,3-1.5 Hz, 1H), 7.52 (d, J = 7.9 Hz, 2H), 7.46- d]pyrimidin-5- 7.34 (m,3H), 7.30-7.21 (m, 3H), 7.12 (d, yl]phenyl)methyl]piperazin-1- J = 7.2Hz, 1H), 5.98 (s, 1H), 4.55-4.53 (m, yl]ethoxy)ethoxy]propyl]pyrido[2,3-1H), 3.75-3.60 (m, 11H), 3.46 (s, 2H), 3.30b]indol-9-yl)piperidine-2,6-dione (d, J = 7.4 Hz, 2H), 3.14 (m, 1H),3.05-2.96 (m, 1H), 2.89-2.79 (m, 1H), 2.67-2.38 (m, 11H), 2.23-2.11 (m,3H), 2.08-2.04 (m, 6H), 1.61-1.48 (m, 2H), 1.31 (s, 1H)

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications, andnon-patent publications referred to in this specification areincorporated herein by reference in their entireties, including U.S.provisional application nos. 62/694,931, filed Jul. 6, 2018, 62/820,641,filed Mar. 19, 2019, and 62/863,954, filed Jun. 20, 2019.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20220348556A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

We claim:
 1. A compound of formula I-d:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is a bivalentmoiety selected from a covalent bond, —CH₂—, —CHCF₃—, —SO₂—, —S(O)—,—P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—, —C(S)—, or

X² is a carbon atom or silicon atom; X³ is a bivalent moiety selectedfrom —CR₂—, —NR—, —O—, —S—, or —Si(R₂)—; R¹ is hydrogen, deuterium,halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —N(R)₂, —P(O)(OR)₂,—P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃, or anoptionally substituted C₁₋₄ aliphatic; each R is independently hydrogen,or an optionally substituted group selected from C₁₋₆ aliphatic, phenyl,a 4-7 membered saturated or partially unsaturated heterocyclic having1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or: two Rgroups on the same nitrogen are taken together with their interveningatoms to form a 4-7 membered saturated, partially unsaturated, orheteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen,independently selected from nitrogen, oxygen, and sulfur; each R² isindependently hydrogen, deuterium, —R³, halogen, —CN, —NO₂, —OR, —SR,—N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,—C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂, —OC(O)R,—OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—,—N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂,—N(R)P(O)(OR)₂, —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;each R³ is independently an optionally substituted group selected fromC₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; Ring A is a tricyclic ring selected from

wherein each of Ring B, Ring D, and Ring C is independently a fused ringselected from 6-membered aryl, 6-membered heteroaryl containing 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5to 7-membered saturated or partially unsaturated carbocyclyl, 5 to7-membered saturated or partially unsaturated heterocyclyl ring with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur; L¹ is a covalentbond or a C₁₋₃ bivalent straight or branched saturated or unsaturatedhydrocarbon chain wherein 1-2 methylene units of the chain areindependently and optionally replaced with —O—, —C(O)—, —C(S)—, —CR₂—,—CFR—, —CF₂—, —NR—, —S—, —S(O)₂— or —CR═CR—; m is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, or
 16. L is a covalent bond or abivalent, saturated or unsaturated, straight or branched C₁₋₅₀hydrocarbon chain, wherein 0-6 methylene units of L are independentlyreplaced by —C(D)(H)—, —C(D)₂-, -Cy-, —O—, —NR—, —Si(R)₂—, —Si(OH)(R)—,—Si(OH)₂—, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—,—C(O)—, —S(O)—, —S(O)₂—, —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—,—OC(O)NR—, —NRC(O)O—,

wherein: each -Cy- is independently an optionally substituted bivalentring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7membered saturated or partially unsaturated carbocyclylenyl, a 4-7membered saturated or partially unsaturated spiro carbocyclylenyl, an8-10 membered bicyclic saturated or partially unsaturatedcarbocyclylenyl, a 4-7 membered saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, a 4-7 membered saturated or partiallyunsaturated spiro heterocyclylenyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclicsaturated or partially unsaturated heterocyclylenyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, a5-6 membered heteroarylenyl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclicheteroarylenyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; each of n is independently 1, 2, 3, 4, 5,6, 7, 8, 9, or 10; and TBM is a target binding moiety.
 2. The compoundof claim 1, wherein: Ring A is a tricyclic ring selected from

wherein each of Ring B and Ring C is independently a fused ring selectedfrom 6-membered aryl containing 0-3 nitrogens, 5 to 7-membered saturatedor partially unsaturated carbocyclyl, 5 to 7-membered saturated orpartially unsaturated heterocyclyl ring with 1-3 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur,or 5-membered heteroaryl with 1-3 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur; Ring D is a fused ring selected fromaryl containing 0-3 nitrogens, saturated or partially unsaturatedcarbocyclyl, saturated or partially unsaturated heterocyclyl ring with1-2 heteroatoms independently selected from nitrogen, oxygen, silicon,or sulfur, or heteroaryl with 1-3 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur; and

is a single or double bond; m is 0, 1, 2, 3, 4, 5, 6, 7, or
 8. 3. Thecompound of claim 1 or 2, wherein: Ring A is a tricyclic ring selectedfrom

wherein each of Ring B and Ring C is independently a fused ring selectedfrom 6-membered aryl containing 0-2 nitrogens, 5 to 7-membered saturatedor partially unsaturated carbocyclyl, 5 to 7-membered saturated orpartially unsaturated heterocyclyl ring with 1-2 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur,or 5-membered heteroaryl with 1-3 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur;

is a single or double bond; and m is 0, 1, 2, 3, 4, 5, 6, 7, or
 8. 4.The compound of any one of claims 1-3, wherein X¹ is selected from acovalent bond, —CH₂—, —C(O)—, or


5. The compound of any one of claims 1-4, wherein R¹ is hydrogen,deuterium, halogen, —OR, —SR, —S(O)R, —S(O)₂R, —NR₂, or an optionallysubstituted C₁₋₄ aliphatic.
 6. The compound of any one of claims 1-5,wherein Ring A is a tricyclic ring selected from


7. The compound of any one of claims 1-6, wherein each of Ring B andRing C is independently selected from 6-membered aryl containing 0-2nitrogen atoms, 6-membered partially saturated carbocyclyl, or6-membered partially saturated heterocyclyl with 1-2 heteroatomsindependently selected from nitrogen, oxygen or sulfur.
 8. The compoundof any one of claims 1-7, wherein R¹ is hydrogen, deuterium, halogen,—OR, —SR, —S(O)R, —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄aliphatic.
 9. The compound of any one of claims 1-8, wherein R² ishydrogen, —R³, halogen, —OR, —SR, —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,—C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,—C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R,—N(R)C(O)N(R)₂, or —N(R)S(O)₂R.
 10. The compound of any one of claims1-9, wherein L is a bivalent, saturated or unsaturated, straight orbranched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methylene units of L areindependently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—,—C(O)—, —S(O)—, —S(O)₂—, —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—,—OC(O)NR—, —NRC(O)O—,


11. The compound of any one of claims 1-10, wherein L¹ is a covalentbond or a C₁₋₃ bivalent straight or branched saturated or unsaturatedhydrocarbon chain wherein 1-2 methylene units of the chain areindependently and optionally replaced with —O—, —C(O)—, —C(S)—, —CR₂—,—CFR—, —CF₂—, —NR—, —S—, or —S(O)₂—.
 12. The compound of any one ofclaims 1-11, wherein R¹ is hydrogen, deuterium, halogen, —OR, —SR,—S(O)R, —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic. 13.The compound of any one of claims 1-12, wherein Ring B and Ring C is a6-membered aryl containing 0-2 nitrogen atoms.
 14. The compound of anyone of claims 1-13, wherein TBM is a target binding moiety that binds toa target protein selected from the group listed in paragraph [00292].15. The compound of claim 14, wherein TBM is a target binding moietythat binds to one or more of SMARCA2, SMARCA4, and PBRM1.
 16. Thecompound of claim 14, wherein TBM is a target binding moiety that bindsto MERTK.
 17. A pharmaceutical composition comprising a compoundaccording to any one of the preceding claims, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier,adjuvant, or vehicle.
 18. A method of degrading a target protein in abiological sample comprising contacting the sample with the compound ofany one of claims 1-13, or a pharmaceutically acceptable salt thereof,wherein the target protein is selected from group listed in paragraph[00292].
 19. A method of treating a target protein-mediated disorder,disease, or condition in a patient comprising administering to saidpatient the pharmaceutical composition of claim
 17. 20. The method ofclaim 19, wherein the disorder is selected from an autoimmune disorder,an inflammatory disorder, a proliferative disorder, an endocrinedisorder, a neurological disorder, or a disorder associated withtransplantation.
 21. The method of claim 20, wherein the disorder is aproliferative disorder.
 22. The method of claim 21, wherein theproliferative disorder is a cancer.
 23. The method of claim 22, whereinthe cancer is squamous-cell carcinoma, basal cell carcinoma,adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas,cancer of the bladder, bowel, breast, cervix, colon, esophagus, head,kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach;leukemias; benign and malignant lymphomas, particularly Burkitt'slymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; multiple myeloma, sarcomas, includingEwing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma,myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas,astrocytomas, oligodendrogliomas, ependymomas, gliobastomas,neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas,pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, andSchwannomas; bowel cancer, breast cancer, prostate cancer, cervicalcancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer,thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer,stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma,Hodgkin's disease, Wilms' tumor or teratocarcinomas, T-lineage Acutelymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL),Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-BLymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL,Philadelphia chromosome positive ALL and Philadelphia chromosomepositive CML.